Pesticides and insect repellents

ABSTRACT

Provided herein are screening methods for identifying compounds for use as repellents, e.g., as alternatives to DEET, and as pesticides. Further provided are one or more compounds identified using the screening methods described herein, and compositions containing such compounds.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority benefit of U.S. Provisional Patent Application No. 62/968,817, filed Jan. 31, 2020. The disclosure of this application is hereby incorporated herein by reference in its entity.

STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH

This invention was made with government support under 1R01DC014092-01A1 awarded by NIH. The government has certain rights in the invention.

TECHNICAL FIELD

The present disclosure relates generally to the field of pesticides and insect repellents, and more specifically to methods of identifying such pesticides and repellents and the compounds being identified.

BACKGROUND

Blood-feeding insects, such as mosquitoes, transmit deadly pathogens like malaria parasites, dengue viruses, and filarial worms to hundreds of millions of people every year. Insect repellents can be very effective in reducing vectorial capacity by blocking the contact between blood-seeking insects and humans; however, they are seldom used in disease-prone areas of Africa and Asia due to high costs and need for continuous application on skin.

N,N-Diethyl-m-toluamide (DEET) is an example of an insect repellent used in the developed world for more than sixty years. The use of DEET as an insect repellent, however, has several drawbacks. For example, DEET is a solvent capable of melting several forms of plastics, synthetic fabrics, painted and varnished surfaces (Krajick et al., Science, 313: 36, 2006). Additionally, DEET has been shown to inhibit mammalian cation channels and human acetylcholinesterase, which is also inhibited by carbamate insecticides commonly used in disease endemic areas (Corbel et al., BMC Biol, 7, 2009). These concerns are enhanced by the requirement of direct and continuous application of DEET to every part of exposed skin in concentrations that can be as high as 30-100%. Several instances of increased resistance to DEET have also been reported in flies, Anopheles albimanus, and Aedes aegypti (Reeder et al., J Econ Entomol, 94: 1584, 2001; Klun et al., J Med Entomol, 41: 418, 2004; Stanczyk et al., Proc Natl Acad Sci USA, 107: 8575, 2010). Thus, what is needed in the art are alternative compounds to DEET that can be used as insect repellents but are safe for human use, and methods of identifying such alternatives.

Moreover, mosquito strains with resistance to pyrethroid insecticides, the main line of defense against mosquitoes in developing countries, are spreading (Butler et al., Nature, 475: 19, 2011). Increased resistance to pyrethroid insecticides also necessitates discovery of new alternatives.

BRIEF SUMMARY

In one aspect, provided is a method for identifying a compound that is a pesticide and/or a repellent. In some embodiments, provided is a method for identifying a compound that is a repellent, for example, an insect repellent, such as an alternative to DEET. In some embodiments, provided is a method for identifying a compound that is a pesticide, for example, a pesticide similar to pyrethroid.

In another aspect, provided are compositions each comprising at least one compound identified according to any one of the methods described herein. The compound identified and compositions thereof may be suitable for use as repellents and/or pesticides. In some embodiments, compounds identified and compositions thereof may be useful in agricultural control. In some embodiments, compounds identified and compositions thereof may be useful in treating and/or controlling pest insects to plants, cereals, oilseeds, fruits and vegetables, and other corps. Compounds identified and compositions thereof can be used to treat and/or control pest insects, including but not being limited to, pests of field crops (such as aphids, armyworms, and blister beetles, and see more examples on https://entomology.ca.uky.edu/fieldcrop), fruits pests (such as fruit flies, codling moth, controlling apple pests, grape insects, green fruitworms, and leafhoppers, and see more examples on https://entomology.ca.uky.edu/fruit), vegetable pests (such as beet armyworms, cabbage insects, seedcorn maggots, and whiteflies, and see more examples on https://entomology.ca.uky.edu/vegetable), and liverstock pests (such as horn flies and cattle, and horse bots, and see more examples on https://entomology.ca.uky.edu/livestock). In some embodiments, compounds identified and compositions thereof may be useful in household pest control. Exemplary household pests include but are not limited to termites and cockroaches.

DESCRIPTION OF THE FIGURES

The present application can be best understood by references to the following description taken in conjunction with the accompanying figures.

FIGS. 1A and 1B are representative images showing the mosquitoes landed on an attractive 37 C heat pad, by overlaying the photo frames taken over 5 minutes. FIG. 1A is the positive control where a filter paper with solvent acetone (air dried) is placed on top of the 37 C heat pad placed in a cage of 20 female Aedes aegypti mosquitoes. FIG. 1B is a filter paper with one of the identified repellents from Table A, dissolved at 3% concentration with acetone (air dried).

FIG. 2 shows percentage Mean repellency, compared to solvent control, of different test compounds at 3% (v/v or w/v in acetone) from Table A using the assay in FIG. 1 . A horizontal line reflects 90% repellency. N=3 trials, ˜20 female Aedes aegypti/trial. Several fall above the horizontal line which reflects 90% repellency. The repellency data is used to generate partially the training set for the Machine Learning.

FIG. 3 shows percentage repellency, compared to solvent control, of different test compounds at 3% (v/v or w/v in acetone) from Table A and B using the assay in FIG. 1 . N=1 trial, with ˜20 female Aedes aegypti. Several fall above the horizontal line which reflects 90% repellency. The compounds are randomly selected from repellent predictions in Table A and B performed by Machine Learning.

FIG. 4 illustrates mosquito behavioral assay glove setup. The assay glove is assembled in the following order: rubber glove with window cut into the hand, magnet glued around the cut window, control or test odor treatment mesh, three spacer magnets that prevent mosquitoes from biting through to the hand, untreated mesh to prevent mosquitoes from touching the treated mesh, and finally a top magnet. One metal clip is then used on each side of the stack to further reinforce the arrangement of magnets and mesh.

FIG. 5 shows a series of representative still photographs from specific time-points of video assaying landing of female Aedes aegypti on solvent treated and repellent treated netting in the hand-in-glove assay.

DETAILED DESCRIPTION

As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an insect” includes a plurality of such insects and reference to “the compound” includes reference to one or more compounds, and so forth.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. Although any methods and reagents similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, the exemplary methods and materials are now described.

The following description is presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific materials, techniques, and applications are provided only as examples. Various modifications to the examples described herein will be readily apparent to those of ordinary skill in the art, and the general principles defined herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Thus, the various embodiments are not intended to be limited to the examples described herein and shown, but are to be accorded the scope consistent with the claims.

Screening Methods

Provided herein are screening methods for identifying one or more compounds that are natural repellents, e.g., as alternatives to DEET. Provided herein are also screening methods for identifying one or more compounds that are natural insecticides, e.g., the ones that are structurally similar to pyrethroid insecticides.

In some embodiments, chemical features that are predictive of repellency are identified and used to predict new chemicals from natural sources. In some embodiments, models rank the chemicals allowing for the selection of a smaller set of candidates that are suitable for experimental validation.

In some embodiments, structural features of known pyrethroid insecticides are used to develop models that predict new naturally sourced chemicals with insecticidal activity and therefore identifies several new potential insecticides.

Candidate Compounds

The screening methods provided herein may be used to screen one candidate compound or a plurality of candidate compounds. The one or more candidate compounds may be natural or synthetic compounds. For example, the one or more candidate compounds may be from bacterial, fungal, plant and animal extracts that are commercially available or readily produced. The one or more candidate compounds can also be chemically-modified compounds, such as by acylation, alkylation, esterification, or acidification of natural compounds. The one or more candidates compounds screened in the methods described herein may be pre-selected based on one or more criteria. For example, a set of compounds with structural similarities to known insect repellents, like DEET, may be screened and selected for use in the methods described herein. A computation method may be used to select such candidate compounds. Other criteria used for selecting the one or more candidate compounds include the environmental impact of the compounds, regulatory approval of the compounds for human consumption (e.g., FDA-approval), and the smell of the compounds (e.g., natural fragrances, aromas, or odors).

Compounds Identified and Compositions Thereof

The following compounds have been identified using the methods and systems described herein. One or more of such identified compounds may be used in an insect repellent composition or a pesticide composition.

Insect Repellent Composition

In some embodiments, the compound identified as an insect repellent according to the methods and systems described herein are selected from Table A and Table B. In some aspects, provided are insect repellent compositions comprising one or more, two or more, or three or more compounds selected from Table A and Table B below.

In some embodiments, the compounds identified as an insect repellent according to the methods and systems described herein consist of core structures that are conserved in the structures of several compounds.

In some embodiments, the compounds identified have a core structure selected from the groups of Table A.1 or Table A.2 and are conserved in the structure of compounds selected from Table A.

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table A.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table A.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table A.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table A.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table A.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compound is

In some embodiments, the compounds have a core structure selected from the group consisting of

(A6.3) from Table A.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table A.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table A.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

(A8.3). In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table A.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of s ci

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table A.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from

In some embodiments, the compounds have a core structure of

(A10.3). In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table A.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table A.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table A.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table A.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table A.2. In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds identified have a core structure selected from the groups of Table B.1 or Table B.2 and conserved in the structure of compounds selected from Table B.

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table B.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table B.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table B.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table B.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table B.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table B.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table B.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table B.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table B.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table B.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table B.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table B.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table B.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table B.2. In some embodiments, the compounds have a core structure of

In some embodiments, the compound is selected from the group consisting of

In some embodiments, the compounds have a core structure selected from the group consisting of

from Table B.2. In some embodiments, the compound is selected from the group consisting of

TABLE A Compound ID Group SMILES ZR1 A1.1 C═CCn1c(═O)cc(C)c2cccc(C)c21 ZR18 A1.1 CCCC(═O)c1c(C)c2ccccc2n1C ZR20 A1.1 C═CCc1c(C)[nH]c2ccc(C)cc2c1═O ZR58 A1.1 C═CCc1c(C)[nH]c2c(C)cccc2c1═O ZR94 A1.1 Cc1c(C(═O)C(C)C)c2ccccc2n1C ZR134 A1.1 CCc1c(C)[nH]c2cc(C)ccc2c1═O ZR207 A1.1 CCc1[nH]c2cccc(C)c2c(═O)c1C ZR322 A1.1 CCCn1c(═O)cc(C)c2ccccc21 ZR360 A1.1 CCc1c(C)[nH]c2ccc(C)cc2c1═O ZR385 A1.1 Cc1cc(═O)n(C(C)C)c2ccccc12 ZR489 A1.1 Cc1ccc2c(c1)nc(C(C)C)c(═O)n2C ZR4 A1.2 CCOC(═O)c1c(C)[nH]c2ccc(C)cc12 ZR23 A1.2 Cc1nc(C)n(C)c(═O)c1-c1ccccc1 ZR28 A1.2 Cc1nc(C)c(-c2ccccc2)c(═O)[nH]1 ZR91 A1.2 CC1═C(C(═O)c2ccoc2)C(C)(C)CC═C1 ZR97 A1.2 CC(C)c1cnc(-c2ccccn2)[nH]c1═O ZR107 A1.2 Cc1nc(═O)c(-c2ccccc2)c(C)n1C ZR151 A1.2 CCOC(═O)c1c(C)n(C)c2ccccc12 ZR197 A1.2 CC(═O)c1c(C)cc(C)c(-c2ncc[nH]2)c1C ZR219 A1.2 CCOC(═O)c1c(C)[nH]c2ccccc12 ZR223 A1.2 CCOc1ccc2[nH]c(C)c(C(C)═O)c2c1 ZR255 A1.2 C═C1C(═C(C)C)C(═O)N[C@H]1c1ccccc1 ZR364 A1.2 C═C1C(═C(C)C)C(═O)N[C@@H]1c1ccccc1 ZR378 A1.2 CCc1c(C)[nH]c2cc(OC)ccc2c1═O ZR432 A1.2 COc1ccc2[nH]cc(C(C)C)c(═O)c2c1 ZR458 A1.2 C/C═C1/C(═C(C)C)C(═O)N[C@H]1c1ccccc1 ZR9 A1.3 C═CCn1c(═O)c(CC)c(C)c2ccccc21 ZR30 A1.3 CCOC(═O)c1c(C)n(C)c2ccc(C)cc12 ZR236 A1.3 CCOc1ccc2c(c1)c(C(C)═O)c(C)n2C ZR307 A1.3 CCc1[nH]c(═O)cc2cc(OC)c(OC)cc12 ZR466 A1.3 C/C1═C\C(═O)c2c(C)coc2C/C(C)═C/CC1 ZR479 A1.3 C═CCc1c(C)[nH]c2c(OC)cccc2c1═O ZR486 A1.3 CCc1[nH]c2c(OC)cccc2c(═O)c1CC ZR494 A1.3 COc1cccc2[nH]c(C)c(C(C)C)c(═O)c12 ZR2 A2.1 COC(═O)[C@@]1(N)CCc2ccccc21 ZR8 A2.1 COC(═O)[C@]1(N)CCc2ccccc21 ZR35 A2.1 CC(═O)N1c2ccccc2C(═O)C[C@@H]1C ZR79 A2.1 CC[C@@]1(C)C(═O)N(C)c2ccc(O)cc21 ZR82 A2.1 CCn1c(═O)c(C)c(O)c2ccccc21 ZR95 A2.1 CCc1c(O)c2ccccc2n(C)c1═O ZR120 A2.1 CC(C)N1C(═O)[C@H](N)c2ccccc21 ZR130 A2.1 CC[C@]1(C)C(═O)N(C)c2ccc(O)cc21 ZR136 A2.1 CC[C@@H]1C(═O)c2ccccc2N(C)C1═O ZR170 A2.1 COc1cc(OC)c2c(c1)[C@@H](C)CC2═O ZR172 A2.1 COc1cc(OC)c2c(c1)[C@H](C)CC2═O ZR176 A2.1 CC[C@H]1C(═O)c2ccccc2N(C)C1═O ZR213 A2.1 CC(C)N1C(═O)COc2ccccc21 ZR230 A2.1 CC(C)N1C(═O)[C@@H](N)c2ccccc21 ZR251 A2.1 NCCn1ncc2ccccc2c1═O ZR316 A2.1 CC1═NN(c2ccccc2)C(═O)[C@@H]1N ZR351 A2.1 CCn1ccc2ccc(OC)cc2c1═O ZR359 A2.1 CC1═NN(c2ccccc2)C(═O)[C@H]1N ZR382 A2.1 CC(═O)N1c2ccccc2C(═O)C[C@H]1C ZR406 A2.1 COc1ccc(OC)c2c1C(═O)C[C@H]2C ZR425 A2.1 COc1ccc(OC)c2c1C(═O)C[C@@H]2C ZR435 A2.1 CCn1c(C)nc2ccccc2c1═O ZR444 A2.1 CC1═[N+](C)c2ccccc2N(C)C(═O)C1 ZR487 A2.1 CC1(C)C(═O)C═CO[C@@]1(C)c1ccccc1 ZR3 A2.2 CC[C@]1(C)C(═O)c2ccccc2N(C)C1═O ZR5 A2.2 CC[C@@]1(C)C(═O)c2ccccc2N(C)C1═O ZR29 A2.2 CCOC(═O)[C@]1(C)C(C)═Nc2ccccc21 ZR37 A2.2 COc1cc2c(cc1OC)CC(═O)NCC2 ZR61 A2.2 CCOC(═O)[C@@]1(C)C(C)═Nc2ccccc21 ZR68 A2.2 COC(═O)[C@@H]1CCC(═O)c2ccccc21 ZR69 A2.2 COC(═O)[C@H]1CCC(═O)c2ccccc21 ZR110 A2.2 CC(═O)N(C)c1ccc2c(c1)CCCCC2═O ZR117 A2.2 CCc1cc2cc(OC)ccc2[nH]c1═O ZR124 A2.2 COc1cccc2c1CCC[C@@]2(O)C(C)═O ZR128 A2.2 CN1CCC[C@H](C(═O)c2cccnc2)C1═O ZR142 A2.2 CC(═O)N1CC[C@H](C═O)c2ccccc21 ZR148 A2.2 CC(═O)N1CC[C@@H](C═O)c2ccccc21 ZR150 A2.2 CC(═O)c1ccc2c(c1)N(C(C)═O)CCO2 ZR159 A2.2 CC(═O)c1ccc([C@H]2CNC(═O)C2)cc1C ZR163 A2.2 COc1cccc2c1CCC[C@]2(O)C(C)═O ZR173 A2.2 Cc1cc(N2CCCC2═O)Ccc1C#N ZR195 A2.2 C═CN1CC[C@H](C(═O)c2ccccc2)C1═O ZR209 A2.2 COC(═O)c1ccc2c(c1)CCCCC2═O ZR211 A2.2 C═CC[C@@H]1C(═O)CCc2ccc(OC)cc21 ZR217 A2.2 C═CC(═O)N1CCOCc2ccccc21 ZR234 A2.2 CC(═O)N1c2ccccc2[C@H](C═O)C[C@@H]1C ZR237 A2.2 CN1CCC[C@@H](C(═O)c2cccnc2)C1═O ZR246 A2.2 CC(═O)c1ccc([C@@H]2CNC(═O)C2)cc1C ZR292 A2.2 COc1cc(OC)c2c(c1)C(C)(C)CC2═O ZR313 A2.2 CC(═O)N1c2ccccc2[C@@H](C═O)C[C@@H]1C ZR318 A2.2 COc1cc2c(cc1OC)CC(═O)NC═C2 ZR325 A2.2 O═C1CNC(═O)[C@@]12CCCc1ccccc12 ZR330 A2.2 CNC(═O)c1cc2c(cc1C)OCCCO2 ZR345 A2.2 COC(═O)C[C@H]1COc2cc(O)ccc21 ZR402 A2.2 CC(═O)Nc1ccc2c(c1)CCN2C(C)═O ZR423 A2.2 CNC(═O)[C@H]1Cc2ccccc2N1C(C)═O ZR427 A2.2 COC(═O)C[C@H]1COc2cccc(OC)c21 ZR451 A2.2 CN1CCC[C@H](C(═O)c2ccncc2)C1═O ZR463 A2.2 CC(═O)N1c2ccccc2NC(═S)C[C@H]1C ZR468 A2.2 CC(═O)N1c2ccccc2[C@H](C═O)C[C@H]1C ZR471 A2.2 CCOc1cc2c(cc1OC)[C@H](N)CC2═O ZR474 A2.2 CCOc1cc2c(cc1OC)[C@@H](N)CC2═O ZR337 A2.3 C═CC(═O)Nc1cccc2c1CCN2C(C)═O ZR346 A2.3 CC(═O)c1cc(N2CCOCC2═O)ccc1N ZR350 A2.3 COc1cc([C@@H]2CNC(═O)C2)ccc1C(C)═O ZR389 A2.3 COc1cc([C@H]2CNC(═O)C2)ccc1C(C)═O ZR492 A2.3 COc1cc([C@H]2CCNC(═O)C2)ccc1C(C)═O ZR6 A3.1 CC(═O)CCc1c(C)[nH]c2ccccc2c1═O ZR11 A3.1 CC(═O)CCc1c(C)[nH]c2ccc(C)cc2c1═O ZR104 A3.1 COc1ccc(C2═CC(═O)C[C@](C)(O)C2)cc1 ZR122 A3.1 CC(═O)c1cc2c(cc1C)N(C(C)═O)C(C)(C)C═C2C ZR135 A3.1 COc1cccc2c(═O)c(CCC(C)═O)c(C)[nH]c12 ZR184 A3.1 COc1ccc(C2═CC(═O)C[C@@](C)(O)C2)cc1 ZR189 A3.1 CC(═O)CCc1c(C)c2cccc(C)c2[nH]c1═O ZR228 A3.1 CC(═O)Nc1ccc2c(c1)C(═O)CC(C)(C)O2 ZR243 A3.1 CC(═O)CCc1c(C)c2ccccc2[nH]c1═O ZR352 A3.1 COc1ccc2[nH]c(C)c(CCC(C)═O)c(═O)c2c1 ZR371 A3.1 CNC(═O)Cn1c(C)cc(═O)c2cccc(C)c21 ZR424 A3.1 CCC(═O)Cc1ccc2[nH]c(C)cc(═O)c2c1 ZR467 A3.1 C/C(Cl)═C/Cc1c(C)[nH]c2ccc(C)cc2c1═O ZR21 A3.2 CC1═CC(C)(C)N(C(C)C)c2cc(C)c(C#N)cc21 ZR43 A3.2 CC(═O)N1c2ccccc2C(C)═CC1(C)C ZR133 A3.2 C═C(C)[C@H]1CC═C(C)C2═CC(═O)[C@H](C)C[C@@]21C#N ZR194 A3.2 C/C═C/C(═O)N1c2ccccc2C(C)═CC1(C)C ZR196 A3.2 CCC(═O)c1ccc2c(c1)C(C)(C)C(═O)N2 ZR221 A3.2 COc1ccc2c(c1)C(C)═CC(C)(C)N2C(C)═O ZR254 A3.2 Cc1ccc(C(C)(C)C)c2oc(═O)cc(C)c12 ZR258 A3.2 Cc1cc(C)c2c(C#N)cn(C(C)(C)C)c2n1 ZR268 A3.2 CC(═O)Cc1cc2ccccc2c(═O)n1C ZR369 A3.2 C═C(C)[C@@H]1CC═C(C)C2═CC(═O)[C@H](C)C[C@@]21C#N ZR383 A3.2 CCCC(═O)c1ccc2c(c1)C(C)(C)C(═O)N2 ZR404 A3.2 C/C═C/C(═O)N1c2ccc(C)cc2C(C)═CC1(C)C ZR454 A3.2 C═C(C)[C@H]1CC═C(C)C2═CC(═O)CC[C@@]21C#N ZR482 A3.2 CC(═O)c1ccc2c(c1)C(═O)CC(C)(C)O2 ZR121 A3.3 COc1ccc2c(c1)CC[C@@]1(C)CC(═O)C═C21 ZR123 A3.3 COc1ccc2c(c1)CC[C@]1(C)CC(═O)C═C21 ZR164 A3.3 Cc1cc2oc(═O)c3c(c2cc1O)CCCC3 ZR190 A3.3 Cc1cc(O)c2c3c(c(═O)oc2c1)CCCC3 ZR212 A3.3 C[C@H]1CC(═O)c2c(-c3ccccc3)n[nH]c2C1 ZR226 A3.3 CNc1c2c(nc3ccccc13)CC(C)(C)CC2═O ZR249 A3.3 CC(═O)C1═C(C)N[C@H](C)[C@H]2Oc3ccccc3[C@@H]12 ZR282 A3.3 Cc1cc(O)c2c3c(c(═O)oc2c1)CC[C@H](C)C3 ZR309 A3.3 Cc1cc(O)c2c3c(c(═O)oc2c1)CC[C@@H](C)C3 ZR462 A3.3 CC[C@@]1(C)Cc2ccccc2-c2nc[nH]c(═O)c21 ZR478 A3.3 C═CCNc1c2c(nc3ccccc13)CC(C)(C)CC2═O ZR7 A4.1 C#CCN(C)C(═O)c1cc(C)n(CC)c1C ZR31 A4.1 C#CCN(CC)C(═O)c1ncoc1C(C)C ZR51 A4.1 C#CCNC(═O)[C@H](C)c1c(C)nn(C)c1C ZR60 A4.1 C═CCN(C)C(═O)c1cnn(CC)c1C ZR62 A4.1 CCOC(═O)/C(═C\N(C)C)c1ccccn1 ZR81 A4.1 COCCNC(═O)c1cnc(C)nc1C ZR87 A4.1 CCN(C(C)═O)c1cccc(C(C)═O)c1 ZR89 A4.1 COC(═O)[C@H](C)n1c(C)cc(C═O)c1C ZR100 A4.1 C#CCN(C)C(═O)c1ccncc1CC ZR102 A4.1 COC(═O)[C@@H](C)n1c(C)cc(C═O)c1C ZR109 A4.1 COCCNC(═O)c1c(C)nn(C)c1C ZR119 A4.1 C═C[C@@H](CC)OC(═O)c1cnn(C)c1C ZR127 A4.1 C═C[C@H](CC)OC(═O)c1cnn(C)c1C ZR131 A4.1 C#CCNC(═O)[C@@H](C)c1c(C)nn(C)c1C ZR199 A4.1 CCOC(═O)[C@H](N)c1ccc(OC)cc1 ZR202 A4.1 COC[C@@H](C)NC(═O)c1cnc(C)cn1 ZR208 A4.1 COC[C@H](C)NC(═O)c1cnc(C)cn1 ZR214 A4.1 C═C[C@H](C)OC(═O)c1cn(C)nc1CC ZR233 A4.1 COCC(═O)N[C@@H](C)c1cnn(C)c1C ZR244 A4.1 C═C[C@H](CC)OC(═O)c1cccc(C)n1 ZR245 A4.1 CCOC(═O)[C@@H](N)c1ccc(OC)cc1 ZR260 A4.1 CCOC(═O)c1ncn(CCOC)c1N ZR266 A4.1 C═C[C@@H](CC)OC(═O)c1cccc(C)n1 ZR287 A4.1 CCOC(═O)c1ccccc1CC(C)═O ZR297 A4.1 COCC(═O)N[C@H](C)c1cnn(C)c1C ZR301 A4.1 C═C[C@@H](C)OC(═O)c1cn(C)nc1CC ZR302 A4.1 C═C(C)COC(═O)c1c(C)cc(C)cc1C ZR333 A4.1 CCOC(═O)c1cnc(CN(C)C)nc1C ZR348 A4.1 CCCc1ncccc1C(═O)N(C)OC ZR370 A4.1 CCN(CC)C(═O)c1ccc(C#N)c(C)n1 ZR392 A4.1 C═CCNC(═O)c1c(C)noc1C(C)C ZR395 A4.1 C#CCNC(═O)Cc1c(C)nn(C)c1C ZR418 A4.1 C═C[C@@H](C)OC(═O)c1ccncc1CC ZR422 A4.1 COC(═O)CCc1c(C)[nH]c(C═O)c1C ZR441 A4.1 CCOC(═O)Cc1c(C)[nH]c(C═O)c1C ZR448 A4.1 C#CC(C)(C)NC(═O)c1ccccc1OC ZR449 A4.1 C═CCN(CC═C)C(═O)c1cc(C)oc1C ZR491 A4.1 CCOc1ccccc1C(═O)N(C)OC ZR19 A4.2 C#C[C@H](C)OC(═O)c1cccc(COC)c1 ZR55 A4.2 CNC(═S)/C(C(C)═O)═C(/C)Nc1ccccc1 ZR56 A4.2 CNC(═S)/C(C(C)═O)═C(\C)Nc1ccccc1 ZR138 A4.2 CCOC(═O)Cc1ccc(C(C)═O)cc1 ZR149 A4.2 COCCCNc1nnc(C)c(C)c1C#N ZR180 A4.2 COC[C@H](C)NC(═O)c1cnc(C)nc1C ZR191 A4.2 CCOC(═O)CCc1c(C)[nH]c(C═O)c1C ZR220 A4.2 COC[C@@H](C)NC(═O)c1cnc(C)nc1C ZR247 A4.2 C#C[C@@H](C)OC(═O)c1cccc(COC)c1 ZR252 A4.2 C═C[C@H](C)OC(═O)c1ccc(C(C)═O)cc1 ZR261 A4.2 C═C[C@@H](C)OC(═O)c1ccc(C(C)═O)cc1 ZR286 A4.2 COc1ccc(C(═O)N(C)CCC#N)cc1 ZR304 A4.2 CCOC(═O)/C═C(\C)c1ccc(OC)cc1 ZR327 A4.2 COCCNC(═O)c1cnc(N(C)C)nc1C ZR357 A4.2 CN[C@@H](C#N)Cc1ccc(OC)c(OC)c1 ZR368 A4.2 CCOC(═O)c1ccc(N(C)CCO)nn1 ZR374 A4.2 CCN(CC)C(═O)NC(═S)c1cccnc1 ZR430 A4.2 CCn1cc(NC(═O)COC)ccc1═O ZR445 A4.2 CC(═O)C[C@@H](C)NC(═O)c1cnn(C)c1C ZR452 A4.2 C═C[C@@H](CC)OC(═O)c1cccnc1OC ZR457 A4.2 Cc1cc(OCC(═O)C(C)(C)C)ccc1C#N ZR459 A4.2 C═C[C@H](CC)OC(═O)c1cccnc1OC ZR481 A4.2 COCC(═O)NCc1ccnc(OC)c1 ZR493 A4.2 C#CC(C)(C)OC(═O)c1ccc(OC)cc1 ZR495 A4.2 CCOC(═O)/C═C(/C)c1ccc(OC)cc1 ZR118 A4.3 CCN(C(═O)CCOC)c1ccc(C#N)cc1 ZR269 A4.3 COC[C@@H](C)NC(═O)c1ccc(C#N)c(C)n1 ZR285 A4.3 C═CCN(CC═C)C(═O)NC(═S)c1ccccc1 ZR298 A4.3 COC[C@H](C)NC(═O)c1ccc(C#N)c(C)n1 ZR437 A4.3 COCCCNC(═O)c1ccc(C#N)c(C)n1 ZR446 A4.3 C═CCN(CC═C)C(═O)NC(═S)c1cccnc1 ZR497 A4.3 CCOC(═O)O/C(C)═C\c1ccccc1OC ZR10 A5.1 CO[C@H](C)C(═O)Nc1c(C(C)C)c(C)nc2ccccc12 ZR101 A5.1 COc1ccc(F)cc1-c1nc(C)ncc1C(C)C ZR139 A5.1 C#C[C@@H](C)N(C)C(═O)c1cc(C)cc2c(C)ccnc12 ZR179 A5.1 Cc1nn(C)c(C)c1[C@H](C)NC(═O)c1cccnc1 ZR215 A5.1 C═CCNC(═O)Cc1coc2c(C)c(C)ccc12 ZR235 A5.1 CCN(CC)C(═O)c1ccc(-c2cccs2)nc1C ZR303 A5.1 CCOC(═O)c1c(C)[nH]c(C)c1-c1ccccc1OC ZR320 A5.1 CCN(C)C(═O)c1cncc(-c2ccccc2C)c1 ZR323 A5.1 COc1ccc2nc(C)c(C(═O)NC(C)C)cc2c1 ZR342 A5.1 CC[C@@H](C)NC(═O)c1cc2cc(OC)ccc2nc1C ZR355 A5.1 CO[C@@H](C)c1ccc(-c2cc(C)c(C)nc2O)cc1 ZR361 A5.1 Cc1nn(C)c(C)c1[C@@H](C)NC(═O)c1cccnc1 ZR373 A5.1 C#CC(C)(C)NC(═O)c1cc(C)nc2c(C)cccc12 ZR377 A5.1 COC[C@@H](C)NC(═O)c1cc(C)nc2ccccc12 ZR393 A5.1 C═CCNC(═O)c1cc2c(C)nn(C)c2nc1C ZR455 A5.1 COCc1c(C(═O)NCC(C)C)oc2ccccc12 ZR490 A5.1 C#C[C@H](C)N(C)C(═O)c1cc(C)cc2c(C)ccnc12 ZR498 A5.1 COC[C@H](C)NC(═O)c1cc(C)nc2ccccc12 ZR499 A5.1 C═CCNC(═O)c1ccc(OC)c2ccccc12 ZR38 A5.2 Cc1ccc2nc(C)c(C(═O)N(C)C(C)C)cc2c1 ZR49 A5.2 CCN(CC)C(═O)c1cc(C)nc2ccccc12 ZR93 A5.2 CCN(CC)C(═O)c1cc(C)nc2ccc(C)cc12 ZR125 A5.2 CCOC1═N/C(═C(/O)c2ccccc2)C(C)═C1C ZR141 A5.2 CC(═O)/C═C(\C)Nc1cccc2c1c(C)c(C)n2C ZR146 A5.2 CCO/C(C)═C1/C(═O)N(CC)c2ccccc21 ZR204 A5.2 CCN(CC)C(═O)c1cc(C)nc2c(C)c(C)ccc12 ZR256 A5.2 C═CCNC(═O)c1oc2ccc(C)cc2c1C ZR289 A5.2 Cc1nc2ccccc2c(C(═O)N(C)C(C)C)c1C ZR326 A5.2 CCN(CC)C(═O)c1cccc2cccnc12 ZR349 A5.2 COC(═O)c1c(C(C)C)nc2ccccc2c1C ZR365 A5.2 CCCN(C)C(═O)c1cc(C)nc2c(C)cccc12 ZR407 A5.2 CCNC(═O)c1c(C)c(-c2ccccc2)n(C)c1C ZR201 COc1cccc(-c2ccnc3c2C(═O)C[C@H](C)C3)c1 ZR12 A6.1 CCOC(═O)c1cc(C)n(CC(═O)NC)c1C ZR24 A6.1 C═C(C)CN(CC)C(═O)c1cc(C(C)═O)cn1C ZR42 A6.1 COc1ccc(NC(═O)C(C)(C)OC)c(C)n1 ZR44 A6.1 CCO/N═C/c1[nH]c(C)c(C(═O)OCC)c1C ZR45 A6.1 CCON═Cc1[nH]c(C)c(C(═O)OCC)c1C ZR54 A6.1 COC[C@@H](C)NC(═O)/C═C/c1c(C)nn(C)c1C ZR76 A6.1 CC[C@](C)(OC)C(═O)Nc1cnc(OC)c(C)c1 ZR77 A6.1 COC[C@H](C)NC(═O)/C═C/c1c(C)nn(C)c1C ZR78 A6.1 CCN(C[C@@H](C)C#N)C(═O)c1cnnc(C)c1 ZR187 A6.1 C═CC(═O)N1CCOC[C@@H]1c1c(C)nn(C)c1C ZR218 A6.1 CC[C@@](C)(OC)C(═O)Nc1ccc(OC)nc1C ZR239 A6.1 CCCC(═O)Nc1c(C(═O)N(C)C)nn(C)c1C ZR241 A6.1 COCC(C)(C)CNC(═O)c1c(C)ncnc1C ZR264 A6.1 Cc1c(NC(═O)C(C)C)c(C(═O)N(C)C)nn1C ZR277 A6.1 CC[C@](C)(OC)C(═O)Nc1ccc(OC)nc1C ZR284 A6.1 COC(═O)C(C)(C)CNC(═O)c1occc1C ZR306 A6.1 C═CC(═O)N1CCOC[C@H]1c1c(C)nn(C)c1C ZR319 A6.1 CC(═O)c1cc(C#N)c(N2CCCC2)nc1C ZR341 A6.1 CCN(CC)C(═O)/C═C/c1c(C)nn(C)c1Cl ZR386 A6.1 COC(═O)[C@@H](Nc1nc(C)cc(OC)n1)C(C)C ZR391 A6.1 CC(═O)c1cc(CNCC(═O)N(C)C)n(C)c1 ZR397 A6.1 CC(═O)/C(═C\c1ccco1)C(═O)CCN(C)C ZR433 A6.1 CCOc1ccc(NC(═O)C(C)(C)OC)c(C)n1 ZR453 A6.1 COC(═O)[C@H](Nc1nc(C)cc(OC)n1)C(C)C ZR460 A6.1 C═CCCCn1nc(C)c([C@@H](C)C(═O)OC)c1C ZR15 A6.2 C#CCN(CC#CC)C(═O)[C@@H](C)n1nc(C)cc1C ZR22 A6.2 C═CCOc1nc(C)c2c(c1C#N)CC(C)(C)OC2 ZR32 A6.2 C═CN1CC[C@H](C(═O)c2cccc(N(C)C)c2)C1═O ZR46 A6.2 CCN(C(C)═O)c1cccc(C(═O)/C═C/N(C)C)c1 ZR67 A6.2 CCN(C(C)═O)c1cccc(C(═O)/C═C\N(C)C)c1 ZR70 A6.2 Cc1nn(C)c(C)c1/C═C/C(═O)N(C)CCC#N ZR86 A6.2 CCOC(═O)c1[nH]c(C)c(CCC(═O)OC)c1C ZR116 A6.2 C═CN1CC[C@@H](C(═O)c2cccc(N(C)C)c2)C1═O ZR126 A6.2 Cc1nn(C)c(C)c1/C═C\C(═O)NC(C)(C)C#N ZR140 A6.2 COCCC(═O)Nc1ccc(C)c(C(═O)N(C)C)c1 ZR154 A6.2 C#CCN(CC#CC)C(═O)[C@H](C)n1nc(C)cc1C ZR161 A6.2 CC(═O)c1cc(C#N)c(N2CCOCC2)nc1C ZR167 A6.2 CCOc1ncccc1C(═O)N(CC)C[C@H](C)C#N ZR238 A6.2 C═CCN(CC═C)C(═O)/C═C/c1c(C)nn(C)c1C ZR293 A6.2 COc1cccc(C(═O)O[C@H](C)C(C)(C)C#N)n1 ZR300 A6.2 COccccc(C(═O)O[C@@H](C)C(C)(C)C#N)n1 ZR380 A6.2 COCCCNC(═O)c1[nH]c(C)c(C(C)═O)c1C ZR410 A6.2 CCOC(═O)c1[nH]c(COC(C)═O)c(CC)c1C ZR483 A6.2 C═C(C)CCOC(═O)c1ccc(C(═O)N(C)C)cc1 ZR496 A6.2 Cc1cc(C(═O)N2CCC[C@@](C)(C#N)C2)cc(C)n1 ZR47 A6.3 C═C[C@H](C)OC(═O)c1cn(C(C)(C)C)nc1C ZR48 A6.3 COCCNC(═O)c1c(C)noc1C(C)C ZR71 A6.3 C═C[C@@H](C)OC(═O)c1cn(C(C)(C)C)nc1C ZR165 A6.3 COC[C@@H](C)NC(═O)c1c(C)noc1C(C)C ZR177 A6.3 CCc1c(C)nn(C)c1NC(═O)C(C)(C)OC ZR181 A6.3 COC[C@H](C)NC(═O)c1c(C)noc1C(C)C ZR203 A6.3 C#CCn1c(C)cc(C(═O)OC(C)(C)C)c1C ZR280 A6.3 CCN(CC)C(═O)/C═C/c1c(C)nn(C)c1C ZR465 A6.3 C═C(C)Cn1nc(C)c([C@@H](C)C(═O)OC)c1C ZR476 A6.3 CCOC(═O)C1═C(C)N/C(═C\N(C)C)C1═O ZR477 A6.3 CCOC(═O)C1═C(C)N/C(═C/N(C)C)C1═O ZR13 A7 C═C(C)CN(C)C(═O)c1cc(CNC(═O)C(C)(C)C)ccc1Cl ZR41 A7 CC(═O)C[C@@H](C)NC(═O)/C═C/c1c(C)nn(CC(C)C)c1Cl ZR155 A7 CC(═O)C[C@@H](C)NC(═O)/C═C\c1c(C)nn(CC(C)C)c1Cl ZR156 A7 CC(═O)C[C@H](C)NC(═O)/C═C\c1c(C)nn(CC(C)C)c1Cl ZR253 A7 CCOc1ccc([C@H]2NC(═S)NC(C)═C2C(═O)NC)cc1OCC ZR265 A7 CCOc1cc(C)c(/C═C2\NC(═S)N(CC)C2═O)cc1C(C)C ZR273 A7 CCCC1═C(C(═O)OCC)[C@@H](c2cccc(OC)c2)NC(═S)N1 ZR290 A7 CCCN1C(═O)/C(═C/c2cc(C(C)C)c(OC)cc2C)NC1═S ZR396 A7 CC(═O)C[C@H](C)NC(═O)/C═C/c1c(C)nn(CC(C)C)c1Cl ZR412 A7 CCOc1cc(C)c(/C═C2/C(═O)N(CC)C(═S)N2C)cc1C(C)C ZR419 A7 COc1ccc([C@H]2NC(═S)NC(C)═C2C(═O)N(C)C)c(OC)c1 ZR488 A7 CCOc1ccc([C@@H]2NC(═S)NC(C)═C2C(═O)NC)cc1OCC ZR14 A8.1 CCCn1nc(C(═O)NC)c2ccccc2c1═O ZR16 A8.1 CCNC(═O)c1nn(CC)c(═O)c2ccccc12 ZR26 A8.1 CCOC(═O)CC[C@]1(C)C(═O)N(C)c2ccccc21 ZR27 A8.1 CCOC(═O)CC[C@@]1(C)C(═O)N(C)c2ccccc21 ZR57 A8.1 COc1ccc2c(c1)CC[C@@](C)(CCC#N)C2═O ZR103 A8.1 CCCn1nc(C(═O)NCC)c2ccccc2c1═O ZR160 A8.1 CC(═O)CC[C@@H]1C(═O)N(C)C(═O)c2ccccc21 ZR162 A8.1 CC(═O)CC[C@H]1C(═O)N(C)C(═O)c2ccccc21 ZR169 A8.1 CC1(C)OC(C)(C)/C(═C\c2ccc(Cl)cc2)C1═O ZR274 A8.1 CO[C@@H](CNC(═O)C(C)(C)C)c1ccccc1Cl ZR321 A8.1 CC(C)NC(═O)c1nn(C)c(═O)c2ccccc12 ZR336 A8.1 COC(═O)C1(c2cccc(Cl)c2)CCC(═O)CC1 ZR438 A8.1 COC(═O)[C@H]1CCC(═O)N(C)[C@@H]1c1ccccc1 ZR440 A8.1 COC(═O)[C@@H]1CCC(═O)N(C)[C@H]1c1ccccc1 ZR447 A8.1 COC(═O)C1(c2ccc(C═O)cc2)CC═CC1 ZR500 A8.1 CCC(═O)Nc1ccc2c(c1)C(C)(C)C(═O)N2C ZR33 A8.2 C═C1N(C(═O)c2ccccc2)N═C(C)C1(C)C ZR74 A8.2 CCC(═O)N1N═C(C)C[C@]1(O)c1ccccc1 ZR80 A8.2 CCC(═O)N1N═C(C)C[C@@]1(O)c1ccccc1 ZR111 A8.2 CCC(═O)N1N═C(C)C[C@]1(O)c1cccnc1 ZR231 A8.2 CC1═NN(C(═O)C(C)C)[C@@](O)(c2cccnc2)C1 ZR248 A8.2 CC(═O)N1N═C(C)C[C@@]1(O)c1ccccc1 ZR250 A8.2 CCC(═O)N1N═C(C)C[C@@]1(O)c1cccnc1 ZR259 A8.2 CCC1═N[C@@H](c2ccccc2Cl)N(O)C1(C)C ZR267 A8.2 CC[C@@H]1C(═O)C(C)(C)C(═O)O[C@H]1c1ccccc1 ZR279 A8.2 CCC1═N[C@H](c2ccccc2Cl)N(O)C1(C)C ZR344 A8.2 Cc1ncc([C@@](C)(O)c2ccccc2)n1C ZR415 A8.2 CC1═NN(C(═O)C(C)C)[C@@](O)(c2ccccc2)C1 ZR429 A8.2 CC(C)N1Cc2cc(Cl)ccc2O[C@@H](C)C1═O ZR485 A8.2 CCn1nc(C(═O)NC)c2ccccc2c1═O ZR145 A8.3 CCOC(═O)Cn1c(C)cc(═O)c2cc(C)cc(C)c21 ZR178 A8.3 COCCNC(═O)c1nn(C)c(═O)c2ccccc12 ZR278 A8.3 CC(═O)Nc1ccc2c(c1)N(C)C(═O)C(C)(C)CO2 ZR295 A8.3 CCOC(═O)c1c(/N═C/N(C)C)c(C#N)c2n1CCCC2 ZR296 A8.3 CCOC(═O)c1c(N═CN(C)C)c(C#N)c2n1CCCC2 ZR308 A8.3 CCCc1cc(═O)oc2cc(OC(C)C)c(Cl)cc12 ZR334 A8.3 COC(═O)C(C)(C)[C@]1(c2ccc(OC)cc2)CCC(═O)O1 ZR335 A8.3 CCC1═NN(C(═O)C(C)C)[C@](O)(c2cccc(OC)c2)C1 ZR338 A8.3 CCn1nc(C(═O)NCCOC)c2ccccc2c1═O ZR401 A8.3 CCc1cc2c(C)c(CC)c(═O)oc2cc1OCC(C)═O ZR416 A8.3 CC(C)NC(═O)[C@]1(C)CC(c2ccccc2Cl)═NO1 ZR17 A9 CCOc1ccccc1[C@@H]1NC(═S)NC(C)═C1C(C)═O ZR25 A9 CCN1C(═O)CC[C@@H](C(═O)NC)[C@@H]1c1ccccc1Cl ZR50 A9 CCOc1ccccc1[C@H]1NC(═S)NC(C)═C1C(C)═O ZR85 A9 CC1═C(C(═O)N(C)C)[C@H](c2ccc(C)cc2)NC(═S)N1 ZR106 A9 COc1ccc(Cl)cc1-c1ccc([C@@H](C)NC(C)═O)cc1 ZR132 A9 CC1═C(C(═O)N(C)C)[C@@H](c2ccc(C)cc2)NC(═S)N1 ZR144 A9 CC(═O)C1═C(C)NC(═S)N[C@@H]1/C═C/c1ccccc1 ZR232 A9 CC1═C(C(═O)N(C)C)[C@@H](c2ccccc2)NC(═S)N1 ZR270 A9 CCOC(═O)C1═C(C)N(C)C(═S)N[C@@H]1c1ccccc1 ZR291 A9 CCOC(═O)C1═C(C)N(C)C(═S)N[C@H]1c1ccccc1 ZR314 A9 CCOC(═O)C1═C(c2ccccc2)NC(═S)N[C@@H]1CC ZR315 A9 CC(═O)c1cccc(N2C(C)═CC(C)(C)N═C2S)c1 ZR343 A9 CCC(═O)c1cccc(—n2nc(C)c(CC(C)═O)c2C)c1 ZR347 A9 CCN1C(═O)/C(═C/c2ccc(OC)c(C)c2)N(C)C1═S ZR358 A9 CC1═C(C(═O)N(C)C)[C@H](c2ccccc2)NC(═S)N1 ZR363 A9 CCN1C(═O)CC[C@@H](C(═O)NC)[C@@H]1c1cccc(Cl)c1 ZR376 A9 CCC(═O)[C@H](C#N)[C@@H](c1ccco1)c1ccccc1OC ZR384 A9 Cc1nn(C)c(C)c1[C@@H](C)C(═O)N(C)[C@H](C)c1ccc(Cl)cc1 ZR390 A9 CCC[C@@H]1NC(═S)N(c2ccccc2)C(C)═C1C(C)═O ZR394 A9 CCC1═C(C(═O)OC)[C@H](c2ccccc2)NC(═S)N1 ZR408 A9 CC(C)(C)n1cccc(/C═C/C(═O)c2ccccc2)c1═S ZR409 A9 CCOCC(═O)N(CC)[C@@H](c1ccc(Cl)cc1)c1cccnc1 ZR414 A9 CCC[C@H]1NC(═S)N(c2ccccc2)C(C)═C1C(C)═O ZR470 A9 COc1cc(C)c(C(═O)N(C)c2ccccc2)cc1C(C)C ZR34 A10.1 CCOC(═O)CCc1ccncc1C(═O)OC ZR52 A10.1 COC[C@H](C)C(═O)Nc1cccc(C)c1C(C)═O ZR73 A10.1 CCC(═O)Nc1cccc(C(═O)N(C)OC)c1 ZR88 A10.1 COC(C)(C)C(═O)Nc1ccc(C(C)═O)cn1 ZR90 A10.1 COc1cc(NC(═O)CC(C)═O)cc(OC)c1 ZR112 A10.1 CC#CCOC(═O)c1cncc(OC(C)C)c1 ZR113 A10.1 COc1ccc(OC)c(NC(═O)CC(C)═O)c1 ZR137 A10.1 COc1cc(NC(═O)[C@@H](C)OC)cc(OC)c1 ZR143 A10.1 COc1ccc(NC(═O)CC(C)═O)cc1OC ZR147 A10.1 COC[C@@H](C)C(═O)Nc1cccc(C)c1C(C)═O ZR168 A10.1 C═CC[C@@H](OC(C)═O)c1ccc(OC)c(OC)c1 ZR182 A10.1 C═CCN(CC═C)C(═O)c1cc(OC)cc(OC)c1 ZR192 A10.1 CON(C)C(═O)c1ccc(C)c(NC(C)═O)c1 ZR193 A10.1 COc1cc(NC(═O)[C@H](C)OC)cc(OC)c1 ZR222 A10.1 COc1ccc(NC(═O)[C@H](C)C(C)═O)cc1 ZR227 A10.1 COc1ccc(NC(═O)CC(C)═O)c(OC)c1 ZR257 A10.1 C═CC[C@H](OC(C)═O)c1ccc(OC)c(OC)c1 ZR272 A10.1 C═CCNC(═O)/C═C/c1cc(OC)ccc1OC ZR275 A10.1 COc1cccc(NC(═O)CC(C)═O)c1OC ZR299 A10.1 CON(C)C(═O)C[C@@H](NC(C)═O)c1ccccc1 ZR312 A10.1 CCC(═O)Oc1ccc(C(═O)CC)cc1OC ZR356 A10.1 COc1ccc(NC(═O)[C@@H](C)C(C)═O)cc1 ZR387 A10.1 C═CCCC(═O)N(C)c1cc(OC)cc(OC)c1 ZR388 A10.1 CCOCC(═O)Nc1cccc(C)c1C(C)═O ZR400 A10.1 CCOC(═O)c1cc(C)nn(CCOC)c1═O ZR411 A10.1 COC(═O)C[C@@H](N)c1ccc(OC)cc1OC ZR421 A10.1 CON(C)C(═O)c1ccc(NC(C)═O)cc1 ZR442 A10.1 C═CCNC(═O)Cc1cc(OC)ccc1OC ZR456 A10.1 COCCOc1ccc(O)cc1C(═O)N(C)C ZR461 A10.1 C═CCc1cc(C(═O)NC2CC2)cc(OC)c1OC ZR480 A10.1 C═CCN(CC═C)C(═O)c1ccc(OC)cc1OC ZR484 A10.1 CCCOCC(═O)Nc1cccc(C)c1C(C)═O ZR39 A10.2 CO[C@@H](C)C(═O)NCc1ccc(C(C)═O)c(C)n1 ZR53 A10.2 COC(═O)CCc1cc(OC)ccc1NC(C)═O ZR63 A10.2 CO[C@H](C)C(═O)NCc1ccc(C(C)═O)c(C)n1 ZR65 A10.2 COC(═O)C[C@@H](NC(C)═O)c1ccc(OC)cc1 ZR92 A10.2 COC(═O)C[C@H](NC(C)═O)c1ccc(OC)cc1 ZR96 A10.2 COCCCC(═O)Oc1c(C)cc(C#N)cc1C ZR152 A10.2 CCOC(═O)C(═Cc1cccnc1)C(═O)OCC ZR153 A10.2 COc1ccc(CNC(═O)CC(C)═O)cc1OC ZR183 A10.2 CCNC(═O)COc1ccc(C#N)cc1OCC ZR271 A10.2 CCOC(═O)C(═Cc1ccncc1)C(═O)OCC ZR294 A10.2 CCOc1cc(C═O)ccc1O[C@H](C)C(═O)N(C)C ZR311 A10.2 CCOc1cc(C═O)ccc1OCC(═O)N(C)C ZR353 A10.2 CCOc1cc(C═O)ccc1O[C@@H](C)C(═O)OC ZR405 A10.2 CCOc1cc(C═O)ccc1O[C@@H](C)C(═O)N(C)C ZR420 A10.2 C═CCc1cc(C═O)ccc1OCC(═O)OCC ZR436 A10.2 CCOc1cc(C═O)ccc1O[C@H](C)C(═O)OC ZR469 A10.2 CCOC(═O)C(═Cc1ccc(OC)cc1)C(═O)OCC ZR59 A10.3 COc1ccc(C)nc1NC(═O)[C@H](C)OC ZR66 A10.3 COc1ccc(C)nc1NC(═O)[C@@H](C)OC ZR166 A10.3 COc1ccc(OC)c([C@H](C)NC(C)═O)c1 ZR198 A10.3 COc1ccccc1C(═O)[C@H](C)NC(C)═O ZR224 A10.3 COc1ccc(OC)c([C@@H](C)NC(C)═O)c1 ZR225 A10.3 CCOC(═O)[C@@H](C(═O)N(C)C)c1ccccc1 ZR242 A10.3 CCOC(═O)[C@H](C(═O)N(C)C)c1ccccc1 ZR288 A10.3 C═CCO[C@H](C)C(═O)N(C)c1cccc(C)n1 ZR310 A10.3 CC(═O)Nc1c(C)cccc1C(═O)OC(C)C ZR329 A10.3 COc1ccc(C)cc1NC(═O)CC(C)═O ZR362 A10.3 C═CCOc1[nH]nc(C)c1CC(═O)OCC ZR403 A10.3 COc1ccccc1C(═O)[C@@H](C)NC(C)═O ZR36 A11 COCCC(═O)N(C)Cc1c(C)[nH]c(C(═O)OC)c1C ZR40 A11 COc1ccc(C(═O)N(C)CC#N)c(OCC(C)C)c1 ZR75 A11 CCOC(C)(C)C(═O)Nc1cccc(C(═O)N(C)C)c1C ZR114 A11 COc1cc(/C═C/C(═O)NC[C@H](C)C#N)cc(OC)c1 ZR115 A11 COc1cc(/C═C/C(═O)NC[C@@H](C)C#N)cc(OC)c1 ZR158 A11 CC[C@@H](OC)C(═O)Nc1ccc(OC)c(C(═O)N(C)C)c1 ZR175 A11 CC[C@H](OC)C(═O)Nc1ccc(OC)c(C(═O)N(C)C)c1 ZR186 A11 CCOc1cc(C(═O)N(C)CCC(═O)NC)ccc1OC ZR262 A11 CCN(C[C@@H](C)C(═O)OC)C(═O)c1ccc(OC)cc1OC ZR331 A11 CCOC(═O)/C(═N\Nc1cc(C)ccc1OC)C(C)═O ZR379 A11 COCCCNC(═O)/C(C#N)═C/c1ccc(OC)c(C)c1 ZR398 A11 CCOC(═O)/C═C/c1cnccc1NC(═O)C(C)(C)C ZR439 A11 CCOC(C)(C)C(═O)Nc1ccc(OC)cc1C#N ZR64 A12 CCOC(═O)c1cnc(N)nc1CC ZR72 A12 CONC(═O)c1c(C)noc1C(C)C ZR98 A12 CCNC(═O)c1c(N)cnn1C(C)C ZR108 A12 CCn1c(N)ccc1C(═O)OC ZR188 A12 CCOC(═O)[C@@H]1NC(C)═CC(C)═C1N ZR210 A12 CCOC(═O)c1cc(N)nn1CC ZR281 A12 CCOC(═O)C(C)(C)n1cc(N)cn1 ZR324 A12 CCOC(═O)c1c(C)ccnc1C ZR443 A12 CCOC(═O)[C@H]1NC(C)═CC(C)═C1N ZR450 A12 CCCn1ncc(N)c1C(═O)N(C)C ZR472 A12 CCOC(═O)c1c(N)c(C)nn1CC ZR83 A13 CCc1c(C═O)c(C)n(-c2cc(C)cc(C)c2)c1C ZR84 A13 CCc1c(C═O)c(C)n(-c2cccc(C)c2C)c1C ZR99 A13 CCc1c(C═O)c(C)n(-c2ccc(C)cc2)c1C ZR129 A13 CCc1c(C═O)c(C)n(-c2cc(C)ccc2C)c1C ZR157 A13 CCc1c(C═O)c(C)n(-c2ccc(C)cn2)c1C ZR185 A13 CCc1c(C═O)c(C)n(-c2cccc(C)n2)c1C ZR200 A13 CCc1c(C═O)c(C)n(-c2cccc(C)c2)c1C ZR216 A13 CCc1c(C═O)c(C)n(-c2ccccn2)c1C ZR229 A13 CCc1c(C═O)c(C)n(-c2cc(C)ccn2)c1C ZR240 A13 CCc1c(C═O)c(C)n(-c2ccc(C)c(C)c2)c1C ZR283 A13 CCc1c(C═O)c(C)n(-c2cccnc2)c1C ZR305 A13 CCc1c(C═O)c(C)n(-c2c(C)cccc2C)c1C ZR332 A13 CCc1c(C═O)c(C)n(-c2cccc(OC)c2)c1C ZR354 A13 CCc1c(C═O)c(C)n(-c2ccc(C)cc2C)c1C ZR381 A13 CCc1c(C═O)c(C)n(-c2ccccc2C)c1C ZR105 A14 C═C(C)c1ccc2c(c1)C(═O)C[C@H]1[C@](C)(C#N)CCC[C@@]21C ZR205 A14 C═C(C)c1ccc2c(c1)C(═O)C[C@@H]1[C@](C)(C#N)CCC[C@@]21C ZR367 A14 CCOC(═O)[C@H](C#N)[C@@H](c1ccccc1OC)[C@H]1CCOC(C)(C)C1 ZR399 A14 CCOC(═O)[C@@H](C#N)[C@H](c1ccccc1OC)[C@@H]1CCOC(C)(C)C1 ZR431 A14 C═C(C)c1ccc2c(c1)C(═O)C[C@H]1[C@]2(C)CCC[C@@]1(C)C#N ZR464 A14 CCOC(═O)[C@H](C#N)[C@H](c1ccccc1OC)[C@H]1CCOC(C)(C)C1 ZR473 A14 CCOC(═O)[C@H](C#N)[C@H](c1ccccc1OC)[C@@H]1CCOC(C)(C)C1 ZR171 A15 CCN(Cc1ccccc1Cl)C(═O)COC ZR174 A15 COC(═O)CN(C)Cc1cc(Cl)ccc1OC ZR206 A15 C═CCCC(═O)NC[C@@H](OC)c1ccccc1Cl ZR263 A15 COCC[C@@H](NC(═O)[C@@H](C)OC)c1ccc(Cl)cc1 ZR276 A15 COCC[C@H](NC(═O)[C@H](C)OC)c1ccc(Cl)cc1 ZR317 A15 COCC[C@@H](C)N[C@H](C(═O)OC)c1ccccc1Cl ZR328 A15 COCC[C@H](C)N[C@@H](C(═O)OC)c1ccccc1Cl ZR339 A15 CCOCC(═O)NC[C@@H](OC)c1ccccc1Cl ZR340 A15 COCC(═O)N(C)Cc1cccc(Cl)c1 ZR366 A15 CCOCC(═O)NC[C@H](OC)c1ccccc1Cl ZR372 A15 COCC[C@H](C)N[C@H](C(═O)OC)c1ccccc1Cl ZR375 A15 CCCC(═O)NC[C@@H](OC)c1ccccc1Cl ZR413 A15 COCC[C@@H](NC(═O)[C@H](C)OC)c1ccc(Cl)cc1 ZR417 A15 C═CCCC(═O)NC[C@H](OC)c1ccccc1Cl ZR426 A15 COCC[C@@H](C)N[C@@H](C(═O)OC)c1ccccc1Cl ZR428 A15 COCC(═O)NCCc1ccc(OC)cc1Cl ZR434 A15 COCC[C@H](NC(═O)[C@@H](C)OC)c1ccc(Cl)cc1 ZR475 A15 CO[C@H](CNC(C)═O)c1ccccc1Cl

TABLE A.1 Images of 6 conserved cores of several compounds in Table A.

TABLE A.2 2 Structures of conserved core of several groups of compounds in Table A. Group Core Structure A1.1

A1.2

A1.3

A2.1

A2.2

A2.3

A3.1

A3.2

A3.3

A4.1

A4.2

A4.3

A5.1

A5.2

A6.1

A6.2

A6.3

A7

A8.1

A8.2

A8.3

A9

A10.1

A10.2

A10.3

A11

A12

A13

A14

A15

TABLE B Com- pound ID Group SMILES NR0125155 B1 CCOC(═O)c1ccc(cn1)OC NR0126694 B1 CCOC(═O)c1cc(n(n1)CO)C NR0267404 B1 c12c([C@H](CCC2═O)O)cccc1OC NR0279863 B1 [C@@]1(O[C@@H]1C)(c1oc(═O)c(cc1)C)C NR0315700 B1 C1═C(C(═O)C═C(C1═O)C)OCC NR0327396 B1 c12c([C@@H](NC(═O)C2)C)cncc1OC NR0333355 B1 c12c(C[C@H](CC2═O)C)occ1C NR0344725 B1 C1(═CC(═O)C═C(C1═O)C)OCC NR0350800 B1 [C@]1(c2c(NC1═O)cccc2)(OC)CC NR0376327 B1 c12c(C[C@@H]([C@@H](C1═O)O)C)occ2C NR0379358 B1 c12c([C@H](CC)O)cncc1CCC2═O NR0044097 B2 C[C@]1(Cc2c(cc(c([n+]2)N)C(═O)[O−])CO1)C NR0047023 B2 C[C@@]1(CC2═C([C@H](CC(═O)N2)c2ccccc2OC)C(═O)C1)C NR0047653 B2 CCOC(═O)c1cc2c(nc1NC(═O)C)C[C@](OC2)(C)C NR0065044 B2 C[C@H]1CC(═C(C2=N[C@](Cc3c2cccc3)(C)C)C(═O)C1)[O−] NR0074832 B2 CCOC(═O)c1cc2c(nc1C)C[C@@](CC2═O)(C)C NR0075036 B2 Cc1c2c3ccccc3nc2c2c(n1C)C[C@@](CC2═O)(C)C NR0087381 B2 Cc1c2c(c(c(n1)OCC═C)C#N)C[C@](OC2)(C)C NR0093187 B2 CCOC(═O)c1cc2c(nc1N)C[C@](OC2)(C)C NR0099165 B2 CC(═C)COc1c(cc2c(n1)C[C@](OC2)(C)C)C#N NR0123554 B2 CC(═O)c1c2c(c(c3c1CCCN3)C(═O)C)NCCC2 NR0124999 B2 CC1═C([C@@H](CC(═O)N1C)c1ccccc1)C(═O)OC NR0125000 B2 CC1═C([C@H](CC(═O)N1C)c1ccccc1)C(═O)OC NR0125215 B2 CCOC(═O)C1═C(N(C(=S)N[C@@H]1c1ccccc1)C)C NR0125216 B2 CCOC(═O)C1═C(N(C(=S)N[C@H]1c1ccccc1)C)C NR0129020 B2 CCC/N═C(/c1c(═O)c2ccccc2n(c1[O−])C)C NR0129021 B2 CC[C@@H](C)/N═C(\c1c(═O)c2ccccc2n(c1[O−])C)C NR0129022 B2 CC[C@H](C)/N═C(\c1c(═O)c2ccccc2n(c1[O−])C)C NR0131472 B2 C[C@]1(Cc2c(c(c3ccccc3[n+]2)NC)C(═O)C1)C NR0141474 B2 CC(═O)Nc1c2ccccc2nc2c1C(═O)C[C@@](C2)(C)C NR0213862 B2 C1(=NC(C(═O)N1)(C(C)C)C)c1cc(ccc1C(═O)OC)C NR0394059 B2 c12c(c(c(═O)n(c1cccc2)C)CC(═O)[C@H](C)C)OC NR0157773 B3 Cc1cc2c(c(c1CCO)C)C(═O)[C@@H]([C@H]2O)C NR0159002 B3 Cc1cc2c(c(c1CCO)C)C(═O)[C@@](C2)(C)CO NR0234310 B3 c12c(cc(c(c1C)CCO)CO)C[C@@H](C2═O)C NR0234958 B3 [C@]1(C(═O)c2c(C1)cc(c(c2C)CCO)C)(CO)C NR0245839 B3 c12c(C(=O)[C@]([C@H]1O)(C)C)c(c(cc2[C@@H](C)C)OC)C NR0266911 B3 c1(c(cc2c(c1C)C(═O)[C@@](C2)(C)CO)C)CCOC NR0277472 B3 c12c(cc(c(c1C)CCO)C)C[C@H](C2═O)C NR0278246 B3 c12c(C(═O)[C@@H]([C@@H]2O)C)cc(c(c1C)CCO)C NR0309630 B3 c12C(═O)[C@](Cc1cc(c(c2C)CCO)C)(O)C NR0319104 B3 c12c(cc(c(c1C)CC(═O)O)C)C[C@@H](C2═O)C NR0325443 B3 c12c([C@@H]([C@@H](C2═O)C)O)cc(c(c1C)CCO)C NR0340230 B3 c12c(C(═O)[C@H]([C@@H]2O)C)cc(c(c1C)CCO)C NR0351917 B3 c12c(cc(c(c1C)CO)C)C[C@H](C2═O)C NR0352723 B3 c12c(c(c3c(c2)C(=O)OCC3)C)C[C@]([C@H]1O)(CO)C NR0365273 B3 c12c(cc(c(c1C)CCO)C)COC2═O NR0377154 B3 c12c([C@H]([C@@H](C2═O)C)O)cc(c(c1C)CCO)C NR0382953 B3 [C@]12(c3c([C@]([C@H]1O)(C)C)ccc(c3C(═O)OC2)C)C NR0391441 B3 c12c([C@H]([C@](C1═O)(C)C)O)cc1c(c2C)CCOC1═O NR0395222 B3 c12C(═O)[C@@](Cc1cc(c(c2C)CCOC)C)(CO)C NR0396964 B3 c12c([C@H]([C@H](C2═O)C)O)cc(c(c1C)CCO)C NR0044830 B4 Cc1c2c(═O)cccc(c2c(n1C)C)OC NR0117406 B4 CCOC(═O)c1c(n(c2c1cccc2)C)C NR0125713 B4 CC1=Nc2ccccc2[C@@]1(C)C(═O)OC NR0125714 B4 CC1=Nc2ccccc2[C@]1(C)C(═O)OC NR0125718 B4 C[C@]1(c2ccccc2N═C1C(═O)OC)C NR0125722 B4 CCC1=Nc2ccccc2[C@@]1(C)C(═O)OC NR0125723 B4 CCC1=Nc2ccccc2[C@]1(C)C(═O)OC NR0125724 B4 CCOC(═O)[C@@]1(c2ccccc2N═C1C)C NR0125725 B4 CCOC(═O)[C@]1(c2ccccc2N═C1C)C NR0124251 B5 CC(═O)N(C)c1cccc(c1)N(C)C(═O)C NR0127793 B5 COc1ccc(c(c1)C(═O)CCCCC(═O)OC)OC NR0156680 B5 CC(═O)CC1═CC(═C(C(═O)C1)OC)OC NR0159258 B5 CC(═O)CCc1cc(c(c(c1)OC)OC)O NR0178126 B5 CC(═O)OCCc1ccc(c(c1)OC)O NR0231396 B5 c1(c(cc(cc1OC)CCNC(═O)C)OC)OC NR0275940 B5 c1(c(C[C@@H](C(═O)OC)CC)nccc1)C(═O)OC NR0286899 B5 n1(c(ccc1C═O)COC)CCCC(═O)OC NR0299464 B5 c1(c(c(ncc1COC(═O)C)C)O)COC NR0305718 B5 c1([C@@H](C(═O)C)OCC)cc(c(cc1)O)OC NR0319487 B5 c1(c(cc(cc1O)OC/C═C(\C)C)OC)C(═O)CCC NR0324098 B5 c1(C(═O)[C@@H](OCC)C)cc(c(cc1)O)OC NR0335556 B5 c1(c(C(═O)OC)cccn1)CC[C@H](C(═O)OC)C NR0343433 B5 c1(c(cc(cc1)OC)/C═C/C)OC(═O)/C(═C\C)C NR0355106 B5 c1(c(ccc(c1)CC(═O)OCC)OC)OC NR0225693 B6 c12c(c(cc(c2)C(═O)C)[C@H](/C═C(\C)C)O)O[C@@](CC1═O) (C)C NR0242527 B6 c12c(c(cc(c1CC[C@](O2)(C)C)O)OC)C(═O)[C@@H](C)C NR0244322 B6 c1(c2c(c(c(c1O)C/C═C(\C)C)OC)C═C[C@@](O2)(C)C)C(═O)C NR0257265 B6 c1(c(c2c(cc1O)O[C@@](C═C2)(C)C)OC)C(═O)[C@H](C)C NR0282312 B6 c12c(c(c(c(c1O)C(═O)C)OC)C/C═C(\C)C)O[C@H](C2)[C@@](O) (C)C NR0296302 B6 c12c(c(c(c(c1)OC)C(═O)[C@@H](CC)C)O)CC[C@](O2)(C)C NR0316888 B6 c12c(cc(o2)[C@](O)(C)C)cc(cc1C[C@@H]([C@](O)(C)C)O)C (═O)C NR0340597 B6 c12c(cc(cc1cc(o2)[C@](O)(C)C)C(═O)C)C(═O)C[C@@H](C)C NR0350774 B6 c12c(c(c(cc1O[C@@]([C@@H]([C@H]2OCC)O)(C)C)OC)C(═O) C)OC NR0356116 B6 c1(c2c(c(cc1O)O)CC[C@](O2)(C)C)C(═O)[C@H](C)C NR0360908 B6 c1(c(c2c(cc1OC)O[C@@](C═C2)(C)C)O)C(═O)[C@@H](C)C NR0372696 B6 c12c(cc(cc1cc(o2)[C@@](O)(C)C)C(═O)C)C(═O)/C═C(/C)C NR0381679 B6 c1(c(c2c(cc1OC)O[C@](CC2)(C)C)O)C(═O)[C@@H](C)C NR0389026 B6 c12c(c(c(c(c1)O)C(═O)[C@@H](CC)C)O)CC[C@](O2)(C)C NR0397278 B6 c12c(C(=O)[C@]([C@H]1OC(=O)C)(C)C)c(c(cc2[C@H](C)C) OC)C NR0044159 B7.1 C[C@@]1(CC(═O)/C(═C/c2ccco2)CO1)C NR0118708 B7.1 COc1ccc(c2c1CCC2═O)OC NR0137650 B7.1 COc1cc2c(cc1OC)C(═O)[C@@H](C2)CO NR0137651 B7.1 COc1cc2c(cc1OC)C(═O)[C@H](C2)CO NR0137653 B7.1 COc1ccc(c2c1C[C@H](C2═O)CO)OC NR0157732 B7.1 C[C@@H]1c2cncc(c2C[C@H]1O)C(═O)OC NR0312780 B7.1 n12[C@H](C(═O)OCc1ccc2C═O)[C@@H](C)C NR0324180 B7.1 c12c(OC(═C(\C)C)\C1═O)ccc(c2)[C@@H](O)C NR0387543 B7.1 c1(C(═O)OCC)c(OC)cccc1OC NR0404007 B7.1 c12c([C@@H]([C@@H](C2)O)C)cncc1C(═O)OC NR0028506 B7.2 CCc1c(cc(c2c1O[C@@H](CC2═O)C)OC)O NR0065095 B7.2 CC(═O)CC(═O)c1ccc2c(c1)OCCO2 NR0155221 B7.2 C[C@]1(CC(═O)c2c(cc(cc2OC)OC)O1)C NR0242262 B7.2 c1(c(c(cc2c1CCO2)OC)C(═O)CCC)O NR0267636 B7.2 c12c(c(ccc1O[C@](C═C2)(C)C)C(═O)C)OC NR0275465 B7.2 [C@@]1(Oc2c(C(═O)C1)cc(cc2)C(═O)C)(CO)C NR0291663 B7.2 c12c(cc(cc1OC)OC)O[C@@H](CC2═O)CC NR0372120 B7.2 C1(═O)c2c(cc(cc2OC)OC)C[C@H](O1)C NR0395063 B7.2 c12c(c(cc(c1)OC)OC)C(═O)C[C@@H](O2)C NR0028758 B7.3 C[C@H]1Cc2cc(cc(c2C(═O)O1)OC)O NR0044299 B7.3 Cc1c2c(c(cn1)CO)CO[C@](O2)(C)C NR0125455 B7.3 CC(═O)N1CCc2cc(c(cc2C1)OC)O NR0143343 B7.3 C[C@H]1CC(═O)c2c(cccc2OC)O1 NR0228317 B7.3 c12c(c(cc(c1)OC)C)c(═O)cc(o2)C NR0260410 B7.3 c1([C@@](OC)(C)C)oc2c(c1)cc(c(c2)C)O NR0265991 B7.3 c12c(O[C@](C[C@@H]1O)(C)C)ccc(c2)C(=O)C NR0330248 B7.3 c12c(O[C@@](CC1═O)(C)C)ccc(c2)OC NR0347291 B7.3 c1(cc2c(O[C@@](C═C2)(C)C)cc1C)C(═O)C NR0347606 B7.3 C12═CO[C@H](CC1═C(C(═O)C═C2OC)C)C NR0036692 B8 Cc1coc2c1C(═O)[C@H]1[C@@](O1)(CCC═C(C2)C)C NR0068326 B8 Cc1c(ccc2c1oc(═O)c1c2CCC1)OC NR0076085 B8 Cc1cc(c2c(c1)oc(═O)c1c2CCCC1)O NR0143400 B8 Cc1coc2c1C(═O)C1═C(CC═C[C@@]1(C2)C)C NR0156325 B8 C[C@]1(CCC2═C(O1)C(═O)c1ccccc1C2═O)C NR0158423 B8 Cc1coc2c1C(═O)[C@@H]1[C@](O1)(CCC═C(C2)C)C NR0158847 B8 Cc1c2c(cc3c1C(═O)CC3)C(═O)OCC2 NR0160396 B8 Cc1coc2c1C(═O)C1═C([C@H]3C[C@H]3[C@@]1(C2)C)C NR0215412 B8 C12═C(C3C(C1(Cc1c(C2═O)c(co1)C)C)C3)C NR0231176 B8 c12c(cc3c(c1O)occ3C)C(═O)C[C@H](C2)C NR0261866 B8 c12c3c(cc(c1CC[C@H](C2═O)C)CO)occ3C NR0281627 B8 [C@]12([C@@H](O1)C(═O)c1c(occ1C)CC(═CCC2)C)C NR0289665 B8 [C@]12(C(═C(CC═C2)C)C(═O)c2c(C1)occ2C)C NR0296403 B8 c12c(c3c(c(c1occ2C)O)CCC[C@@H]3C)C=O NR0318270 B8 c12c(cc3c(c1OC)occ3C)[C@H](C[C@@H](C2═O)C)C NR0328580 B8 [C@@]12(c3c(C(═O)C═C([C@@H]1CCC2)C)c(co3)C)C NR0353785 B8 C12═C(C(═O)c3c(C1═O)cccc3)OC[C@@](C2)(C)C NR0381963 B8 c12c(c3c(cc2occ1C(═O)C)C(═O)CC[C@H]3C)C NR0400624 B8 c12c(c(c3c(c1C═O)[C@H](CCC3)C)OC)occ2C NR0045455 B9 C[C@H]1[C@H](OC(═O)[C@](C1═O)(C)C)c1ccc(c(c1)OC)OC NR0045457 B9 C[C@H]1[C@@H](OC(═O)[C@](C1═O)(C)C)c1ccc(c(c1)OC)OC NR0045458 B9 C[C@@H]1[C@@H](OC(═O)[C@](C1═O)(C)C)c1ccc(c(c1)OC) OC NR0122269 B9 CCOC(═O)[C@@](C)(C)[C@@]1(CCC(═O)O1)c1ccc(cc1)OC NR0122270 B9 CCOC(═O)[C@@](C)(C)[C@]1(CCC(═O)O1)c1ccc(cc1)OC NR0261888 B9 c1(c(cc(cc1)C)OC(═O)[C@H](C)C)C(═C)COC(═O)C NR0368072 B9 C(═O)(Oc1c(cc([C@H](OC(═O)[C@@H](C)C)C═C)cc1)OC) [C@H](C)C NR0380649 B9 c1(/C(═C\OC(═O)[C@@H](C)C)COC(═O)[C@H](C)C)c(cc(cc1) C)O NR0237534 B10 [C@]1(c2c(c(═O)c(c(o2)OC)C)C)([C@@H](C(═CC(═C1)C)C)/C (═C/C(═O)C)C)C NR0290847 B10 [C@]1(c2c(c(═O)c(c(o2)OC)C)C)([C@@H](C(═CC(═C1)C)C)/C (═C/[C@@H](C(═O)CC)C)C)C NR0389247 B10 [C@@]1(c2c(c(═O)c(c(o2)OC)C)C)([C@H](C(═CC(═C1)C)C)/C (═C/CC)C)C NR0389671 B10 [C@@]1(c2c(c(═O)c(c(o2)OC)C)C)([C@H](C(═CC(═C1)C)C)/C (═C/[C@H](C(═O)CC)C)C)C NR0397992 B10 [C@@]1(c2c(c(═O)c(c(o2)OC)C)C)([C@H](C(═CC(═C1)C)C)/C (═C/[C@@H](C(═O)CC)C)C)C NR0013536 B11 Cc1cc(c(c2c1CC[C@@H]1[C@@H]2OC(═O)[C@H]1C)C)O NR0063708 B11 CCc1cc(═O)oc2c1c(cc1c2CC[C@@](O1)(C)C)OC NR0075929 B11 Cc1c(c(═O)oc2c1c(cc1c2CC[C@@](O1)(C)C)O)C NR0078805 B11 CCCc1cc(═O)oc2c1cc1c(c2C)O[C@](CC1═O)(C)C NR0081990 B11 Cc1c2c(cc3c1O[C@](C[C@H]3O)(C)C)c1c(c(═O)o2)CCCC1 NR0089767 B11 Cc1c2c(cc3c1O[C@](C[C@@H]3O)(C)C)c1c(c(═O)o2)CCCC1 NR0155272 B11 Cc1cc(c(c2c1CC[C@@H]1[C@H]2OC(═O)[C@H]1C)C)O NR0155398 B11 Cc1cc(c(c2c1CC[C@@H]1[C@H]2OC(═O)[C@H]1C)C)OC NR0163179 B11 Cc1coc2c1C(═O)[C@H]1[C@@H](C[C@H](C═C1C2)OC)C NR0263142 B11 c12c3c(C(═O)C(═C(\C)C)/O3)ccc1C[C@H](O[C@@H]2O)C NR0269407 B11 c12c3c(ccc1c(═O)c(c(o2)C)C)C[C@H](O[C@@H]3O)C NR0292905 B11 c12c3c(c(═O)c(c(o3)C)C)ccc1C[C@@](OC2)(O)C NR0296386 B11 [C@H]12c3c(C(═O)C═C([C@@H]1[C@H](C[C@@H]2C)OC)C) c(co3)C NR0296705 B11 c12c3c(C(═O)C(═C(\C)C)/O3)ccc1C[C@H](O[C@@H]2OC)C NR0315704 B11 c12c3c(C(═O)[C@@H](O3)[C@H](C)C)ccc1C[C@H](O[C@@H] 2OC)C NR0329981 B11 [C@@H]12[C@@](Oc3c(C1)c(c(cc3)C(═O)C)O)(OC[C@@H] 2C)C NR0043967 B12.1 COc1cc2c(cc1OC)[C@]1(CCCC1)C(═O)OC2 NR0044680 B12.1 CC[C@]1([C@H](O1)c1ccc(cc1)OC)C(═O)OCC NR0044683 B12.1 CC[C@@]1([C@@H](O1)c1ccc(cc1)OC)C(═O)OCC NR0045428 B12.1 CCc1cc2c(c(c(═O)oc2cc1OC)CC)C NR0051562 B12.1 CCCc1c(c2ccc(cc2oc1═O)OCCC)C NR0067011 B12.1 CCCc1c(c2ccc(cc2oc1═O)OC)C NR0086340 B12.1 Cc1cccc2c1nc(c(c2O)CCC(═O)C)C NR0118415 B12.1 C[C@@]1(CCc2cc(ccc2C1═O)OC)C(═O)OC NR0127969 B12.1 COc1ccc2c(c1)C[C@]1(C2═O)CCC(═O)CC1 NR0250065 B12.1 c1(c2c(c(cc1OC)C)oc(═O)c(c2)C)[C@@H](C)C NR0261537 B12.1 [C@]1([C@@H](O1)C)(/C═C(\c1cc(c(c(═O)o1)C)OC)C)C NR0300999 B12.1 O1c2c(C[C@H]1[C@@](O)(C)C)cc(cc2OC)C═O NR0306870 B12.1 c12c(cc(cc2)OCC)oc(═O)c(c1C)C NR0308654 B12.1 c12c(c(cc(c1[C@@H](C)C)O)C)oc(═O)c(c2)C NR0327564 B12.1 c12c(cc(c(c2)C)[C@H](CCC(═O)C)O)occ1C NR0339112 B12.1 c12c(C[C@H](O2)[C@@](O)(C)C)cc(cc1OC)C(═O)OC NR0354553 B12.1 c12c(cc(c(c2)C)C(═O)CCC(═O)C)occ1C NR0399939 B12.1 [C@]1([C@H](O1)C)(/C═C(\c1cc(c(c(═O)o1)C)OC)C)C NR0404162 B12.1 c1(c2c(cc(c1C(═O)C)C)cccc2OC)OC NR0019926 B12.2 C[C@@](C)([C@H](Cc1c(ccc2c1oc(═O)cc2)OC)O)OC NR0043278 B12.2 C/C═C/C(═O)N1c2ccc(cc2C(═C[C@ @] 1(C)C)C)OC NR0064477 B12.2 CCOc1ccc2c(c1)c(c(c(n2)C)CCC(═O)C)O NR0066854 B12.2 Cc1ccc2c(c1)[C@H](C[C@H](N2C(═O)C)C)OC(═O)C NR0077406 B12.2 CCOC(═O)/C═C\1c2cc(c(cc2C[C@@](N1)(C)C)OC)OC NR0134734 B12.2 CC(═O)CCN1Cc2cc(c(cc2[C@H](C1)O)OC)OC NR0143877 B12.2 CCOC(═O)c1c2cc(ccc2oc1[C@](C)(C)C)O NR0144121 B12.2 CCOC(═O)c1c2cc(ccc2oc1[C@](C)(C)C)OC NR0146981 B12.2 CC[NH+](CCO)Cc1cc(═O)oc2c1cc(c(c2)C)Cl NR0146982 B12.2 Cc1cc2c(cc1Cl)c(cc(═O)o2)C[NH+](C)CCO NR0244708 B12.2 [C@H]1(c2c([C@H](CC1═O)C)cc(c(c2)C)OC(═O)C)[C@@H](C) C NR0332520 B12.2 c1(c2c(c(cc1C)OC)C═C[C@@](O2)(C)C)C(═O)OC NR0368343 B12.2 c12c(c(c(c(c1)OC)C/C═C(\C)C)O)c(═O)cc(o2)C NR0385361 B12.2 c12c(c(c(c(c1)OC)C(═O)OC)C)C═C[C@@](O2)(C)C NR0134737 B12.3 COc1ccc2c(c1O)CN1CCC(═O)C[C@H]1C2 NR0134740 B12.3 COc1cc2c(cc1O)CN1CCC(═O)C[C@@H]1C2 NR0134743 B12.3 COc1cc2c(cc1O)C[C@H]1CC(═O)CCN1C2 NR0368062 B12.3 c12c(O[C@@](C(═O)CC[C@H]1C)(C)C)cc(c(c2)O)C NR0021218 B13 Cc1coc2c1C(═O)C[C@@H](C[C@H](C═C(C2)C)OC)C NR0021220 B13 Cc1coc2c1C(═O)C[C@H](C[C@H](C═C(C2)C)OC)C NR0021221 B13 Cc1coc2c1C(═O)C[C@H](C[C@@H](C═C(C2)C)OC)C NR0159429 B13 Cc1coc2c1C(═O)C═C(CCC═C(C2)C)C NR0228234 B13 c12c(c(co1)C)CC═C(C(═O)OC)CCC═C(C2)C NR0235600 B13 c12c(CC(═CCC[C@@H](C(═O)C2)C)C)occ1C NR0258297 B13 C1(═C(c2cocc2)CC[C@@H]1C)C(═O)/C═C(\C)C NR0258982 B13 c12c(c(co1)C)CC═C(C(═O)OC)CCC═C(C2)C NR0295319 B13 c1(C2═C(CC[C@H]2C)C(═O)C)c(cco1)[C@H](C)C NR0298160 B13 c12c(CC(═C[C@H](C[C@@H](CC2═O)C)OC)C)occ1C NR0300156 B13 c12c(CC(═C[C@@H](C[C@H](CC2═O)C)OC)C)occ1C NR0340209 B13 c1(C2═C(CC[C@H]2C(═O)C)C)c(cco1)[C@H](C)C NR0013897 B14 Cc1cc2c(cc1O)[C@]1(CCC(═O)[C@@]([C@@H]1CC2═O)(C)C) C NR0020634 B14 Cc1cc2c(cc1O)[C@]1(CCC(═O)[C@@]([C@H]1CC2═O)(C)C)C NR0043051 B14 C/C(═C\COc1cc2c(cc1Cl)c1c(c(═O)o2)CCCC1)C NR0160334 B14 C/C═C\C(═O)OCCc1c(cc2c(c1C)C(═O)[C@H](C2)C)C NR0230964 B14 [C@]12(c3c(C(═O)C[C@H]1[C@](C(═O)CC2)(C)C)cc(c(c3)OC) OC)C NR0233161 B14 [C@]1(c2c(cc3c(c(═O)c2)cc(c(c3OC)OC)[C@@H](C)C)C═C [C@H]1O)(C)C NR0238967 B14 c1(═O)oc2c(C/C═C(\C)C)c(ccc2cc1[C@](C═C)(C)C)OC NR0271750 B14 c12c3c(c(c(cc3)O)C)CCc1c(c(cc2[C@H](OCC)C)OC)C NR0296309 B14 C12═Cc3c(C(═O)C[C@H]1[C@](CC[C@H]2O)(C)C)cc(c(c3)OC) C NR0300215 B14 c12c([C@@H]([C@@H]([C@@](C2═O)(C)C)O)C)cc2c(c1O)c(cc (c2)OC)C NR0306136 B14 c1(c2c(c(c3c1[C@H](CCC3)C)OC)occ2C)CC(═O)/C(═C\C)C NR0321845 B14 [C@@H]12[C@@](c3c(C(═O)C2)cc(c(c3)C)O)(CCC(═O)[C@@] 1(C)C)C NR0324353 B14 c12c(cc(c(c1C)CCOC(═O)/C═C\C)C)C[C@H](C2═O)C NR0325151 B14 c12c3c(c(cc2ccc(c1C═C(O3)C(═O)[C@@H](C)C)C)[C@H](C)C) O NR0358201 B14 C12═CC(═O)c3c([C@]1(CC[C@@H]([C@@]2(C)C)O)C)cc(c(c3) C)O NR0358588 B14 c12c3c(c(c(c1C(═O)[C@H]([C@@H](O2)C)C)O)C/C═C(/C)C)OC (═O)C[C@@H]3CCC NR0359810 B14 c12c3c(c(c(c1C(═O)[C@@H]([C@H](O2)C)C)O)C/C═C(/C)C)OC (═O)C[C@H]3CCC NR0365939 B14 [C@]1([C@H]2C(═CC(═O)[C@@H]1O)c1c(C(═O)C2)cc(c(c1) OC)C)(C)C NR0368390 B14 c12c(c3c(c(c2O)C/C═C(/C)C)OC(═O)C[C@H]3CCC)O[C@H]( [C@@H](C1═O)C)C NR0373534 B14 c12C(═O)[C@@]([C@@H]([C@@H](c1cc1c(c2O)c(cc(c1)OC)C) C)O)(C)C NR0224764 B15 [C@]12([C@H](CC(═O)C═C1C)C)CC(═O)CC2 NR0268737 B15 [C@@]12(C(═CC(═O)C(═C2)OC)C═C(C(═O)C1)[C@@H](C)C) C NR0272576 B15 C12═C(C(═O)C[C@@H]1[C@H](CC(═O)C(═C2)[C@@H](C)C) C)C NR0313650 B15 [C@]12(C(═C([C@@H]3C(═C1)C(═O)[C@](C3)(C)C)C)C(═O) OC2)C NR0316049 B15 [C@@]12([C@@H](CC(═C2)C(═O)C)CCC(═O)[C@H]1C)C NR0324640 B15 C12═C(C(═O)C═C(C(═C)O2)C(═C)C)CCC[C@@H]1C NR0330884 B15 [C@]12(C(═C(CCC1═O)C)[C@@H]1[C@@H](C═C2)[C@@H] (C(═O)O1)C)C NR0330887 B15 [C@@]12(C(═CC(═O)C[C@H]1C)C)CCC(═O)C2 NR0333649 B15 [C@]12(C(═C([C@@H]3C(═C1)[C@H]([C@](C3)(C)C)O)C)C (═O)OC2)C NR0347374 B15 C12═C(C(═O)C═C(OC1═C)C(═C)C)CCC[C@@H]2C NR0349993 B15 [C@@]1(C(═O)C2═COC(═C(C2═CC1═O)C)C)(CC)C NR0353731 B15 C12═C(C(═O)C(═C[C@@]1(CC(═O)C(═C2)[C@@H](C)C)C) OC)C NR0386491 B15 C12═C3[C@](C═CC(═O)[C@@H]3C)(CC[C@H]2[C@@H](C (═O)O1)C)C

TABLE B.1 Image of 6 conserved cores of several compounds in Table B

TABLE B.2 2 Structures of conserved cores of several groups of compounds in Table B Group Core Structure B1

B2

B3

B4

B5

B6

B7.1

B7.2

B7.3

B8

B9

B10

B11

B12.1

B12.2

B12.3

B13

B14

B15

The compounds may be used alone or in combination with other agents. The compounds of the disclosure may be combined with additional active agent(s), insecticide(s) and the like in traps to reduce the presence of amount of an insect in the environment. For example, compounds of the disclosure may be used in combination with insect traps (e.g., tape, combustibles, electric traps).

In another embodiment, the compounds may be formulated for application to the skin, clothing, bednets, house walls, curtains or other material.

For example, the compounds of the disclosure may be used as repellents or in compositions comprising said repellent compounds and the use of such repellent compounds and compositions in controlling insects.

Liquid formulations may be aqueous-based or non-aqueous (e.g., organic solvents), or combinations thereof, and may be employed as lotions, foams, gels, suspensions, emulsions, microemulsions or emulsifiable concentrates or the like. The formulations may be designed to be slowly release from a patch, canister, emanator or fan-based devices.

The compositions may comprise various combinations of compounds as well as varying concentrations of the compound depending upon the insect to be repelled, the type of surface that the composition will be applied to, or the type of emanator to be used. Typically, the active ingredient compound of the disclosure will be present in the composition in a concentration of at least about 0.0001% by weight and may be 10, 50, 99 or 100% by weight of the total composition. The repellent carrier may be from 0.1% to 99.9999% by weight of the total composition. The dry formulations will have from about 0.0001-95% by weight of the pesticide while the liquid formulations will generally have from about 0.0001-60% by weight of the solids in the liquid phase.

As mentioned above, the compositions may be formulated for administration to a subject. Such formulations are typically administered to a subject's skin. The composition may also be formulated for administration to garments, belts, collars, or other articles worn or used by the subject from whom insects are to be repelled. The formulation may be applied to bedding, netting, screens, camping gear and the like. It will be recognized that the application of the compositions and compounds of the disclosure do not only include human subjects, but include canines, equines, bovines and other animals subject to biting insects. For topical application, the formulation may take the form of a spray formulation, powder or a lotion formulation.

The compounds according to the disclosure may be employed alone or in mixtures with one another and/or with such solid and/or liquid dispersible carrier vehicles.

In other aspects, provided is a method of repelling an insect, comprising dispensing the insect repellent compositions described herein to expose insects to the composition, thereby repelling the insects.

Compositions of Pesticidal Repellents Pesticide

In other embodiments, the compound identified as a spatial repellent and/or pesticide according to the methods and systems described herein are selected from Table C or Table CII. In other aspects, provided are compositions of spatial repellents and/or pesticides, which comprise one or more, two or more, or three or more compounds selected from Table C or Table CII below.

In some embodiments, the compounds identified have a core structure selected from the groups of Table C.1 and are conserved in the structure of compounds selected from Table C.

TABLE C Com- pound ID SMILES RNat6 C[C@]12CC[C@](C[C@H]1C1═CC(═O)[C@H]3[C@]4(CC[C@@H]([C@]([C@H]4 CC[C@]3([C@@]1(CC2)C)C)(C)C)O[C@H]1[C@@H]([C@H]([C@@H]([C@H](O 1)CO)O)O[C@H]1[C@@H]([C@H]([C@@H]([C@H](O1)CO)O)O)O)O)C)(C)C(═O) [O−] RNat9 C[C@]12CC[C@](C[C@H]1C1═CC(═O)[C@H]3[C@]4(CC[C@@H]([C@@]( [C@@H]4CC[C@]3([C@@]1(CC2)C)C)(C)C)O)C)(C)C(═O)[O−] RNat10 CC(═O)O[C@H]1CC[C@]2([C@H]([C@]1(C)C)CC[C@@]1([C@@H]2C(═O)C═C2 [C@]1(CC[C@@]1([C@H]2C[C@@](CC1)(C)C(═O)[O−])C)C)C)C RNat11 C/C(═C\[C@H]1[C@H]([C@@]1(C)C)C(═O)NCc1ccccn1)C RNat12 [C@H]12[C@@H](OC(═O)C2═C)C═C([C@H](CC═C(C[C@H]1OC(═O)/C(═C/C) COC(═O)C)CO)O)C RNat13 [C@@]12([C@]3(C(═CC(═O)[C@@H]1[C@@]1([C@@H](CC2)[C@]([C@H] (CC1)OC(═O)CCCCCCC/C═C\CCCCCC)(C)C)C)[C@H]1[C@@](CC3)(CC[C@] (C1)(C)C)C)C)C RNat14 C[C@H](CCC[C@H](C)C)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]1[C@H]2CC═C 2[C@@]1(CC[C@@H](C2)OC(═O)COc1ccc2c(c1)oc(═O)c1c2CCCC1)C)C RNat16 C[C@]12CC[C@](C[C@H]1C1═CC(═O)[C@@H]3[C@]4(CC[C@@H]([C@] ([C@H]4CC[C@]3([C@@]1(CC2)C)C)(C)C)O)C)(C)C(═O)[O−] RNat17 C[C@]12CC[C@](C[C@H]1C1═CC(═O)[C@H]3[C@]4(CC[C@@H]([C@]([C@H]4 CC[C@]3([C@@]1(CC2)C)C)(C)C)O)C)(C)C(═O)[O−] RNat18 [C@@H]1([C@]([C@H]1/C═C(/C(═O)O)C)(C)C)C[C@@H](C(═C)[C@H](C1═C[C @@H](CC1═O)C)OC(═O)C)OC(═O)c1ccccc1 RNat19 CC1═C(C(═O)C[C@H]1OC(═O)[C@H]1[C@@H]([C@]1(C)C)/C═C(\C)C)C/C═C/ C=C RNat20 C[C@]12CC[C@](C[C@H]1C1═CC(═O)[C@H]3[C@]4(CC[C@@H]([C@]([C@H]4 CC[C@]3([C@@]1(CC2)C)C)(C)C)O[C@H]1[C@@H]([C@H]([C@@H]([C@H](O1) CO)O)O)O[C@H]1[C@@H]([C@H]([C@@H]([C@H](O1)CO)O)O)O)C)(C)C(═O) [O−] RNat22 [C@]12([C@@H]([C@@]([C@H]([C@H](C2)O)O)(C)C)CC═C([C@H]1CC/C(═C/C OC(═O)C)C)C)C RNat23 [C@@]12([C@]3([C@H]([C@@]4([C@H](CC3)[C@]([C@H](CC4)O[C@H]3[C@ H]([C@@H]([C@H]([C@@H](O3)C(═O)O)O)O)O[C@H]3[C@H]([C@@H]([C@H] ([C@@H](O3)O)O)O)C(═O)O)(C)C)C)C(═O)C═C1[C@H]1[C@@](CC2)(CC[C@@] (C1)(C(═O)O)C)C)C)C RNat24 CCOC(═O)[C@@H]1[C@@H]([C@@]1(C)C)/C═C(\C)C RNat25 [C@@]12([C@]3(C(═CC(═O)[C@@H]1[C@@]1([C@@H](CC2)[C@]([C@H](CC1) O)(C)C)C)[C@H]1[C@](CC3)(C(═O)OC)CC[C@](C1)(C)C)C)C RNat26 [C@@]12([C@]3([C@@H]([C@@]4([C@@H](CC3)[C@]([C@H]([C@@H](C4)O) O)(C)C)C)C(═O)C═C1[C@H]1[C@](CC2)(C(═O)OC)CC[C@](C1)(C)C)C)C RNat27 [C@@H]1([C@]([C@@H]1/C═C(\C)C)(C)C)C(═O)O[C@@H]1C(═C(C(═O)C1)C/ C═C\C)C RNat28 [C@@H]1([C@]([C@@H]1/C═C(/C)C)(C)C)C(═O)O[C@@H]1C(═C(C(═O)C1)C/ C═C\CC)C RNat29 [C@@H]1([C@]([C@@H]1/C═C(\C)C)(C)C)C(═O)O[C@H]1C(═C(C(═O)C1)C/ C═C/C═C)C RNat30 [C@@]12([C@]3([C@@H]([C@@]4([C@@H](CC3)[C@]([C@H](CC4)O[C@H]3 [C@@H]([C@H]([C@@H]([C@H](O3)CO)O)O)O)(C)C)C)C(═O)C═C1[C@H]1[C@] (CC2)(C(═O)O[C@H]2[C@@H]([C@H]([C@@H]([C@H](O2)CO)O)O)O)CC[C@] (C1)(C)C)C)C RNat31 [C@@]1([C@H]([C@@H]([C@@]([C@@H](O1)/C═C/C═C\C)(C)C)OC(=O) Cc1ccccc1)O)([C@@H](C(=O)NC/C═C/C═C(/[C@@H]([C@H]([C@@H]1O[C@H] ([C@@H](C1)O)/C═C/C═C/C═C/C(═O)O)C)OC)C)CO[C@@H]1O[C@@H]([C@H] ([C@@H](C1)OC)O)C)O RNat32 [C@@]1([C@H]([C@@H]([C@]([C@@H](O1)/C═C/C═C\C)(C)C)O)OC(=O) Cc1ccccc1)([C@@H](C(=O)NC/C═C/C═C(/[C@@H]([C@H]([C@@H]1O[C@H] ([C@@H](C1)O)/C═C/C═C/C═C/C(═O)O)C)OC)C)CO[C@@H]1O[C@@H] ([C@H]([C@@H](C1)OC)O)C)O RNat33 [C@@]12([C@]3(C(═CC(═O)[C@@H]1[C@@]1([C@@H](CC2)[C@]([C@H](CC1) OC(═O)CCCCCCC/C═C\CCCCCC)(C)C)C)[C@H]1[C@@](CC3)(CC[C@](C1)(C) C)CO)C)C RNat35 C[C@H](CCC[C@H](C)C)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]1[C@H] 2CC═C2[C@@]1(CC[C@@H](C2)OC(═O)COc1ccc2c(cc(═O)oc2c1)c1ccccc1)C)C RNat36 C/C(═C\[C@H]1[C@H]([C@]1(C)C)C(═O)OCc1cccc(c1)Oc1ccccc1)C RNat37 [C@]12([C@@H]3[C@H]([C@H]4[C@](CC3)([C@H](CC4)[C@@H](N(C)C)C)C) CC═C1C[C@H][C@H](C2)O)NC(═O)/C═C(\C)C)C RNat38 [C@@]12([C@]3(C(═CC(═O)[C@H]1[C@@]1([C@@H](CC2)[C@][C@HJ(CC1) O[C@H]1[C@@H]([C@H]([C@@H]([C@H](O1)C(═O)O)O)O)O[C@H]1[C@@H] ([C@H]([C@@H]([C@H](O1)C(═O)O)O)O)O)(C)C)C)[C@H]1[C@@](CC3)(CC [C@@](C1)(C(═O)O[C@H]1[C@@H]([C@H]([C@@H]([C@H](O1)CO)O)O)O)C) C)C)C RNat39 [C@@]12([C@]3(C(═CC(═O)[C@@H]1[C@@]1([C@@H](CC2)[C@]([C@H](CC1) O[C@H]1[C@@H]([C@H]([C@@H]([C@H](O1)C(═O)O)O)O)O[C@H]1[C@@H] ([C@H]([C@@H]([C@H](O1)C(═O)O)O)O)O)(C)C)C)[C@H]1[C@@](CC3)(CC[C @@](C1)(C(═O)O[C@H]1[C@@H]([C@H]([C@@H]([C@H](O1)CO)O)O)O)C)C) C)C RNat41 C[C@H]1CC(═O)C(═C1)[C@H](C(═C)[C@@H](C[C@H]1[C@H]([C@]1(C)C)/ C═C(\C)C(═O)[O−])OC(═O)c1ccccc1)OC(═O)C RNat42 [C@@H]1([C@]([C@@H]1/C═C(/OC(═O)C)C)(C)C)C(═O)O[C@@H]1C(═C(C(═O) C1)C/C═C/C)C RNat43 C[C@]12CC[C@](C[C@H]1C1═CC(═O)[C@@H]3[C@]4(CC[C@H]([C@@]([C@ @H]4CC[C@]3([C@@]1(CC2)C)C)(C)C)O)C)(C)C(═O)OC RNat44 C1[C@@H]([C@@]([C@H]2[C@](C1)([C@@H]1[C@@](CC2)([C@]2(C(═CC1═O) [C@H]1[C@@](CC2)(CC[C@](C1)(C)C(═O)OC)C)C)C)C)(C)C)O RNat45 C[C@]12CC[C@](C═C1C1═CC(═O)[C@@H]3[C@]4(CCC(═O)[C@]([C@H]4CC [C@]3([C@@]1(CC2)C)C)(C)C)C)(C)C(═O)OC RNat46 c1cc(cc(c1)NC(═O)N1C[C@@H]2C[C@H](C1)c1ccc(c(═O)n1C2)c1ccc(cc1)O[C@] (F)(F)F)C#N RNat47 [C@H]1([C@@]([C@@H]1/C═C(/C)C)(C)C)C(═O)O[C@@H]1C(═C(C(═O)C1)C/ C═C\C)C RNat48 [C@]12([C@H]([C@@]([C@H]([C@H](C2)O)O)(C)C)CC═C([C@H]1CC/C(═C/ COC(═O)C)C)C)C RNat49 c12c3nc(co3)[C@H](CC(═O)CCC[C@@H](CC(═O)O[C@H]([C@@H]([C@H](CC= Cc3nc(c(n1)oc2)co3)OC)C)C[C@@H]([C@H](CC[C@H]([C@@H]([C@@H]([C@H] (/C═C/N(C═O)C)C)OC(═O)C)C)OC(═O)[C@@H](COC)OC)C)OC)O)C RNat54 CC[NH2+][C@H]1C[C@H]2C═CCC[C@H]2C[C@@H]1COC(═O)[C@@]12C(═O) c3c(cccc3C(═O)[C@@]1(O2)C/C(═C(\C)C[C@]1(CCCCC1)c1cc[n+]c(c1)NC[NH2+] C)CO)C[C@@H](C)C RNat55 CC1═C(C(═O)C[C@@H]1OC(═O)[C@@H]1[C@H]([C@@]1(C)C)/C═C(\C)C(═O) OC)C/C═C/C═C RNat56 C/C═C/CC1═C([C@H](CC1═O)OC(═O)[C@@H]1[C@H]([C@@]1(C)C)/C═C(\C)C (═O)OC)C RNat57 [C@@H]1([C@]([C@@H]1/C═C(/C(═O)OC)C)(C)C)C(═O)O[C@@H]1C(═C(C(═O) C1)C/C═C\CC)C RNat58 [C@@H]1([C@]([C@@H]1/C═C(\C(═O)OC)C)(C)C)C(═O)O[C@@H]1C(═C(C(═O) C1)C/C═C/C═C)C RNat59 [C@]1([C@@H]([C@H]1C(═O)O[C@@H]1C(═C(C(═O)C1)C/C═C\C)C)/C═C(\C(= O)OC)C)(C)C RNat60 [C@@H]1([C@]([C@@H]1/C═C(/C(═O)OC)C)(C)C)C(═O)O[C@@H]1C(═C(C(═O) C1)C/C═C\C)C RNat61 [C@@H]1([C@]([C@@H]1/C═C(/C(═O)OC)C)(C)C)C(═O)O[C@@H]1C(═C(C(═O) C1)C/C═C\C═C)C RNat62 [C@]123[C@]4(c5c(N2)ccc([C@@H]2[C@]6([C@H]7c8n(c9c(c8CCN7CCC6)cccc9) C2)CC)c5)[C@@H]2[C@@](C[C@H]1C(═O)OC)(CC3)CCCN2CC4 RNat63 [C@@]123[C@@]([C@H](C(═C[C@H](C1═O)[C@H]1[C@@H](C[C@H]2C) [C@@]1(C)C)CO)OC(=O)/C═C/CCCCC)([C@H](C(═C3)C)O)O RNat64 C[C@@]1([C@H]([C@@H]1C(═O)C1═C([O−])CCCC1═O)/C═C(\Cl)Cl)C RNat65 [C@]12([C@H]([C@H]([C@@H]3[C@H](C═C(C(═CC1═O)O2)C)OC(═O)C3═C) OC(═O)/C(═C/C)COC(═O)C)O)C RNat66 C[C@]1([C@H]([C@@H]1C(═O)O[C@@H](C#N)c1cccc(c1)Oc1ccccc1)/C═C(\Br) Br)C RNat67 [C@@]12([C@H]([C@H]([C@H](C2)C)OC(═O)/C═C\c2ccccc2)C═C(CC[C@H]2 [C@@H](C═C(C1═O)C)[C@@]2(C)C)COC(═O)C)OC(═O)C RNat68 C[C@@]1([C@@H]([C@@H]1C(═O)O[C@@H](C#N)c1cccc(c1)Oc1ccccc1)/C═C (\Cl)Cl)C RNat69 C[C@]1([C@H]([C@@H]1C(═O)O[C@@H](C#N)c1cccc(c1)Oc1ccccc1)/C═C(\Cl) Cl)C RNat70 C[C@@]1([C@@H]([C@H]1C(═O)O[C@@H](C#N)c1cccc(c1)Oc1ccccc1)/C═C(\ Cl)Cl)C RNat71 C[C@@]1([C@H]([C@H]1C(═O)O[C@@H](C#N)c1cccc(c1)Oc1ccccc1)/C═C(\Cl) Cl)C RNat72 [C@]12([C@@]([C@H]([C@H](C2)O)[C@@]2(O[C@@H](CC2)[C@@](O)(C)C)C) (CC[C@@]2([C@H]1C[C@@H]([C@@H]1[C@@]2(CC[C@@H]([C@@]1(C)C)O [C@H]1[C@@H]([C@H]([C@@H](CO1)OC(═O)C)OC(═O)C)OC(═O)C)C)O[C@ H]1[C@@H]([C@H]([C@@H](CO1)O)O)O)C)C)C RNat75 [C@]1([C@@]2([C@@H](CC1═O)[C@@]1([C@@H](CC2)[C@](C(═O)CC1)(C)C) C)C)(C1═C[C@H]([C@H]([C@@H](C1)C(═O)C)C(═O)/C(═C/C═C/C(═C1/[C@@] 2([C@@H](CC1=O)[C@@]1([C@@H](CC2)[C@](C(=O)CC1)(C)C)C)C)C)C)/C═C (/c1oc(═O)c(cc1)C)C)O RNat76 COC[C@H]1CCCN1C(═O)CC[C@@H]1CNC(═O)[C@@H]2C[C@@H](C[NH+]12) NC(═O)c1cccc(c1)F RNat77 [C@H]12[C@@H](OC(═O)C2═C)C═C([C@H](CC═C(C[C@H]1OC(═O)/C(═C/C) COC(═O)/C(═C/C)CO)C)O)C RNat78 [C@@]12([C@]3([C@@H]([C@@]4([C@@H](CC3)[C@]([C@H](CC4)O)(C)C)C) C(═O)C═C1[C@H]1[C@@](CC2)(CC[C@@](C1)(C(═O)O)C)C)C)C RNat79 [C@@]12([C@]3([C@@H]([C@@]4([C@@H](CC3)[C@]([C@H](CC4)OC(═O)C) (C)C)C)C(═O)C═C1[C@H]1[C@@](CC2)(CC[C@@](C1)(C(═O)O)C)C)C)C RNat80 [C@@]12([C@]3([C@H]([C@@]4([C@@H](CC3)[C@]([C@H](CC4)O)(C)C)C)C (═O)C═C1[C@H]1[C@@](CC2)(CC[C@@](C1)(C(═O)O)C)C)C)C RNat82 c1cc(cc(c1)F)C(═O)N[C@H]1CCN2[C@@H]1C(═O)Nc1ccc(cc1C2═O)/C═C/c1ccc (cc1)O RNat83 [C@@]1([c@H](C(═O)NC/C═C/C═C(/[C@@H]([C@H][C@@H]2O[C@H]([C@@H] (C2)O)/C═C/C═C/C═C/C(═O)O)C)OC)C)CO[C@H]2C[C@@H]([C@@H]([C@@H] (O2)C)O[C@@H]2C[C@H]([C@H]([C@@H](O2)C)O)OC)OC)(O[C@H]([C@] ([C@H](C1)O)(C)C)/C═C/C═C\C)O RNat84 [C@@]123[C@@]([C@H](C(═C[C@H](C1═O)[C@H]1[C@@H](C[C@H]2C)[C@]1 (C)C)CO)OC(═O)C/C═C/C═C)([C@H](C(═C3)C)O)O RNat85 [C@@]123[C@]([C@@H](C(═C[C@H](C1═O)[C@H]1[C@@H](C[C@H]2C)[C@]1 (COC(═O)c1ccccc1)C)CO)OC(═O)/C(═C\C)C)([C@H](C(═C3)C)OC(═O)C)O RNat86 [C@]1([C@H]([C@H]1C(═O)OC)/C═C(/C=N/O)C)(C)C RNat87 C[C@H](CCC[C@H](C)C)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]1[C@H] 2CC═C2[C@@]1(CC[C@@H](C2)OC(═O)COc1ccc2c(c1)oc(═O)c1c2CCC1)C)C RNat90 Cn1c(cc(═O)c(c1CN1CC[NH+](CC1)C/C═C/c1ccccc1)O)C[NH+]1C[C@H]2C[C@ @H](C1)c1cccc(═O)n1C2 RNat91 CC[C@@H](CCO)/C(═C/C(═O)CCc1cc(c(c2c1C#CC[C@@H](C[C@@]1(C═C3 [C@H](C[C@@H](C[C@@H]3[C@@H]2[C@H]1COC)C)c1cccc(c1)O)CO)/ [NH+]═C(\N)N)O)O[C@H]1CCCC1)CO RNat95 CCN(CC)C(═O)CC[C@@H]1CNC(═O)[C@@H]2C[C@@H](C[NH+]12)NC(═O) c1cccc(c1)F RNat96 [C@@]12([C@H]([C@H]3[C@H](CC2)[C@@]2([C@H](CC3)CC(═O)C(═C2)O) C)CC[C@@H]1[C@@H](Cc1c(cco1)[C@@H](C)C)C(═O)O)C RNat97 [C@]12(C═C(C(═O)C[C@H]2CC[C@@H]2[C@H]1CC[C@]1([C@H]2CC [C@@H]1[C@@H](Cc1c(cco1)[C@@H](C)C)C(═O)O)C)O)C RNat103 c1ccc(c(c1)/C═C\1C(═O)c2ccc(c(c2O1)C[NH+]1C[C@H]2C[C@@H](C1)c1cccc (=O)n1C2)[O−])F RNat104 C[C@H](C)NC(═O)N1C[C@@H]2C[C@H](C1)c1ccc(c(═O)n1C2)c1cccc(c1)[C@ @](F)(F)F RNat105 [C@@]12([C@]3([C@@H]([C@@]4([C@@H](CC3)[C@]([C@H](CC4)O)(C)C)C) C(═O)C═C1[C@H]1[C@@](CC2)(CC[C@@](C1)(C(═O) OCCCCCCCCCCCCCCCCCC)C)C)C)C RNat106 [C@H]1([C@@]([C@@H]1/C═C(/OC(═O)C)C)(C)C)C(═O)O[C@@H]1C(═C(C (═O)C1)C/C═C\C═C)C RNat107 [C@@H]12[C@@]3(C(═CC[C@H]1[C@H]1[C@](CC2)([C@H](CC1)[C@@H](N (C)C)C)C)C[C@H]([C@H](C3)O)NC(═O)/C(═C/C)C)C RNat110 [C@@]12([C@]3([C@@H]([C@H](CC3)[C@@](O[C@H]3[C@@H]([C@H]( [C@@H]([C@H](O3)CO)O)O)O)(CC/C═C(\C)C)C)[C@@H](C[C@@H]1[C@@] 1([C@@H]([C@H](C2)O[C@H]2[C@@H]([C@H]([C@@H]([C@H](O2)CO)O [C@@H]2[C@@H]([C@H]([C@@H]([C@H](O2)CO)O)O)O)O)O)[C@]([C@H] (CC1)O)(C)C)C)O)C)C RNat111 [C@@]123[C@]([C@@H](C(═C[C@@H](C1═O)[C@H]1[C@@H](C[C@H]2C) [C@]1(C)C)COC(═O)c1c(NC(═O)c2c(cccc2)N)cccc1)OC(═O)/C(═C\C)C)([C@H] (C(=C3)C)OC(═O)C)O RNat114 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C[C@]12C[C@H](C[C@](C1)(C)C)N(C2)C(═O)[C@@H]1[C@@H]([C@]1(C) C)/C═C(\Cl)Cl RNat169 C[C@H](C[C@@H](C(═O)[C@@H](C)C(═O)[O−])O)[C@H]1C[C@]2(C═C [C@]3([C@@H]([C@H]4[C@](CCC(═O)[C@@]4(C)C)(C4═C3[C@]2([C@@]1 (CC4═O)[C@@H]1CCCC1)C)C)/C═C/c1ccccc1)O)O RNat170 [C@]12([C@@]([C@H]([C@H](C2)O)[C@@]2(O[C@@H](CC2)[C@](O)(C)C) C)(CC[C@@]2([C@H]1C[C@@H]([C@@H]1[C@@]2(CC[C@@H]([C@@]1 (C)C)O[C@H]1[C@@H]([C@H]([C@@H](CO1)O)O)OC(═O)C)C)O[C@H]1 [C@@H]([C@H]([C@@H]([C@H](O1)CO)O)O)O)C)C)C RNat171 C[C@H](CCC[C@H](C)C)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]1[C@H] 2CC═C2[C@@]1(CC[C@@H](C2)OC(═O)COc1ccc2c(c1)occ(c2═O) c1ccccc1OC)C)C RNat172 CC(═O)O[C@H]1CC[C@]2([C@H]([C@]1(C)C)CC[C@@]1([C@H]2C(═O) C═C2[C@]1(CC[C@@]1([C@@H]2C[C@@](CC1)(C)C(═O)OC)C)C)C)C RNat173 C[C@]12CC[C@](C[C@@H]1C1═CC(═O)[C@@H]3[C@]4(CC[C@@H] ([C@@]([C@@H]4CC[C@]3([C@@]1(CC2)C)C)(C)C)O)C)(C)C(═O)OC RNat174 CC(═O)O[C@H]1CC[C@]2([C@H]([C@]1(C)C)CC[C@@]1([C@@H]2C(═O) C═C2[C@]1(CC[C@@]1([C@@H]2C[C@@](CC1)(C)C(═O)OC)C)C)C)C RNat175 C[C@]12CC[C@](C[C@@H]1C1═CC(═O)[C@H]3[C@]4(CC[C@@H]([C@@] ([C@@H]4CC[C@]3([C@@]1(CC2)C)C)(C)C)O)C)(C)C(═O)OC RNat176 [C@@]12([C@H]3[C@](C(═O)C[C@@H]1[C@@]([C@H](C[C@H]2O)OC(═O)/ C(═C\C)C)(C)C)(O[C@@](C[C@H]3O)(C═C)C)C)C RNat179 [C@@H]12[C@@H]3[C@@](O3)(C[C@H]([C@H]3C(═C)C(═O)O[C@H]3C═C ([C@@H]1O2)CO)OC(═O)/C(═C/C)COC(═O)C)C RNat180 [C@]123[C@@](O1)([C@H]([C@H](C3)C)OC(═O)C)C═C([C@H]([C@H]([C@H] 1[C@@H](C═C([C@@H]2OC(═O)C)COC(═O)C)[C@]1(C)C)OC(═O)C)OC(═O) [C@@H](CC)C)CO RNat181 [C@]1(C(═O)N2[C@@H]1SCC(═C2C(═O)[O−])COC(═O)/C(═C/c1cc(c(cc1) O)O)OC)(NC(═O)CCC[C@@H](C(═O)O)N)OC RNat184 [C@]12([C@H]3[C@]([C@]4(C(═CC3)[C@@H]3[C@@](C(═O)O)(CC4)CC [C@](C3)(C)C)C)(CC[C@@H]1[C@@]([C@@H](O[C@H]1[C@H]([C@@H] (O[C@H]3[C@@H](O[C@H]4[C@H]([C@H]([C@H](CO4)O)O)O)[C@H] ([C@@H](CO3)O)O)[C@@H]([C@H](O1)CO)O)O)[C@H](C2)O)(C)C)C)C RNat185 CCC(═O)O[C@@]1([C@H](C[C@H]2[C@@]1(C[C@@H]([C@]1([C@@H] 2CCC2═CC(═O)C═C[C@]12C)F)O)C)C)C(═O)CCl RNat186 CCC(═O)O[C@@]1([C@H](C[C@H]2[C@@]1(C[C@@H]([C@]1([C@H] 2CCC2=CC(=O)C═C[C@]12C)F)O)C)C)C(=O)CCl RNat187 CCCCC[C@@H](/C═C/[C@H]1CCC(═O)[C@@H]1CCCCCCC(═O)N1CCn2c3ccc (cc3c3c2[C@@H]1CCC3)C)O RNat188 [C@H]12[C@@](C(═O)C(═C[C@@H]3[C@H](CC[C@@]4([C@@H]1O4)C)[C@ @]3(C)C)C)(C[C@H]([C@@H]2OC(═O)C)C)OC(═O)c1ccccc1 RNat189 CCCCC[C@@H](/C═C/[C@H]1CCC(═O)[C@@H]1CCCCCCC(═O)N1CCn2c3ccc (cc3c3c2[C@@H]1CCC3)[C@H]1CCCCC1)O RNat191 CC(═O)O[C@H]1CC[C@]2([C@@H]([C@@]1(C)C)CC[C@@]1([C@@H]2C (═O)C═C2[C@]1(CC[C@@]1([C@H]2C[C@@](CC1)(C)C)C(═O)[O−])C)C)C RNat192 CC(═O)O[C@H]1CC[C@]2([C@@H]([C@]1(C)C)CC[C@@]1([C@H]2C(═O) C═C2[C@]1(CC[C@@]1([C@H]2C[C@@](CC1)(C)C)C(═O)[O−])C)C)C RNat193 [C@@]12([C@]3(C(═CC(═O)[C@@H]1[C@@]1([C@H](CC2)[C@@]([C@H] (CC1)O)(C)C)C)[C@H]1[C@@](CC3)(CC[C@](C1)(C)C)C(═O)O)C)C RNat194 [C@@]123[C@]([C@@H](C(═C[C@H](C1═O)[C@H]1[C@@H](C[C@H]2C) [C@]1(C)C)COC(═O)C)OC(═O)/C═C/C═C\CCCCCCCCC)([C@H](C(═C3)C) OC(═O)C)O RNat195 c1cc(cc(c1)[C@@](F)(F)F)c1ccc2n(c1═O)C[C@H]1C[C@@H]2CN(C1)C(═O) c1ccc(cc1)C#N RNat196 C[C@]12CC[C@](C[C@H]1C1═CC(═O)[C@@H]3[C@]4(CCC(═O)[C@]([C@H] 4CC[C@]3([C@@]1(CC2)C)C)(C)C)C)(C)C(═O)[O−] RNat197 [C@@]12([C@H]([C@H]3[C@H](CC2)[C@@]2(C(═CC3)C[C@H](CC2)O[C@H] 2[C@@H]([C@H]([C@@H]([C@H](O2)CO)O[C@H]2[C@@H]([C@H]([C@@H] ([C@H](O2)CO)O)O)O)O)O)C)C[C@@H]([C@@H]1[C@@H]([C@@H]1N(C [C@H](CC1)C)C)C)O)C RNat198 Cc1ccc2c(c1)c1c3n2CCN([C@@H]3CCC1)CC(═O)N/N═C/C═C/c1ccccc1 RNat199 [C@@]1([C@@H](C(═O)NC/C═C/C═C(\[C@H]([C@H]([C@@H]([C@H] (/C═C\C═C\C═C\C═C(\C(═O)c2c(═O)n(ccc2O)C)C)O)O)C)OC)C)CC)(O[C@H] ([C@@]([C@@H](C1)O)(C)C)/C═C/C═C\C)O RNat200 [C@]123[C@]4([C@@H]([C@@]5([C@@H](CC4)[C@]([C@H](CC5)O[C@H]4 [C@@H]([C@@H](O[C@H]5[C@@H]([C@H]([C@@H]([C@H](O5)CO)O[S@] (═O)(═O)O)O)O)[C@H](CO4)O)O[C@H]4[C@@H]([C@@H]([C@H]([C@@H] (O4)C)O)O)O)(C)C)C)CC[C@@H]1[C@@H]1[C@@](C2)(OC3)O[C@H](C [C@@]1(O)C)/C═C(/C)C)C RNat201 [C@@]12([C@@H]([C@@H](CC[C@H]1CC(═O)C(═C2)[C@@H](C(═O)OC)C) OC(═O)/C(═C\C)C)C(═O)OC)C RNat202 CCCCC/C═C/C═C/C(═O)O[C@H]1C(═C[C@@]23[C@@]1([C@@H](C(═C [C@@H](C2═O)[C@H]1[C@H]([C@]1(C)C)C[C@H]3C)COC(═O)C)O)O)C RNat203 CCCCC/C═C\C═C\C(═O)O[C@H]1C(═C[C@@]23[C@@]1([C@@H](C(═C [C@@H](C2═O)[C@H]1[C@H]([C@]1(C)C)C[C@H]3C)COC(═O)C)O)O)C RNat204 [C@@]123[C@@]([C@H](C(═C3)C)OC(═O)/C═C\C═C\CCCCC)([C@@H](C (═C[C@H](C1═O)[C@H]1[C@@H](C[C@H]2C)[C@]1(C)C)COC(═O)C)O)O RNat205 [C@@]123[C@@]([C@H](C(═C3)C)OC(═O)/C═C/C═C\CCCCC)([C@@H](C (═C[C@H](C1═O)[C@H]1[C@@H](C[C@H]2C)[C@]1(C)C)COC(═O)C)O)O RNat206 [C@@]123[C@@]([C@H](C(═C3)C)OC(═O)/C═C/C═C/CCCCC)([C@@H](C (═C[C@H](C1═O)[C@H]1[C@@H](C[C@H]2C)[C@]1(C)C)COC(═O)C)O)O RNat207 c1ccc(cc1)C(=O)N/C(═C\c1ccccc1F)C(=O)N1C[C@H]2C[C@@H](C1)c1cccc(=O) n1C2 RNat208 c1ccc(cc1)C(=O)N/C(═C\c1ccccc1F)C(=O)N1C[C@@H]2C[C@H](C1)c1cccc(=O) n1C2 RNat209 [C@]123[C@]([C@H](c4cocc4)OC(═O)[C@H]2OC(═O)C)(CC[C@@H](C1═C) [C@@]1([C@@H](O3)[C@H]([C@H]([C@]([C@H]1CC(═O)OC)(C)C)O)OC (═O)C[C@@H](C)C)C)C RNat210 [C@@]123[C@]([C@@H](OC(═O)[C@H]1OC(═O)C)c1cocc1)(CC[C@H]([C@] 1([C@@H](O3)[C@H]([C@H]([C@]([C@@H]1CC(═O)OC)(C)C)O)OC(═O)C [C@@H](C)C)C)C2═C)C RNat211 CC1═C2[C@H](C(═C([C@H](C[C@@H](C(═C[C@@H]([C@@H]([C@@]2(C) C)C[C@@H]1OC(═O)C)OC(═O)C)COC(═O)C)OC(═O)/C═C/c1ccccc1)OC(═O) C)C)OC(═O)C)OC(═O)C RNat212 [C@@H]1([C@@](CCCC1═C)(C)C)CC/C(═C/CC/C(═C/COC(═O)CC(═O)OCC) C)C RNat213 [C@@H]1([C@@](CCCC1═C)(C)C)CC/C(═C/CC/C(═C/COC(═O)CC(═O)OC [C@@H](C)C)C)C RNat214 [C@@H]1([C@@](CCCC1═C)(C)C)CC/C(═C/CC/C(═C/COC(═O)CC(═O)O)C) C RNat215 [C@@H]1([C@@](CCCC1═C)(C)C)CC/C(═C/CC/C(═C/COC(═O)CC(═O)OC)C) C RNat216 [C@@H]1(OC[C@@H]([C@@H]([C@@H]1O)O)O)O[C@H]1CC[C@]23[C@@H] ([C@@]1(C)C)CC═C1[C@@]2(C[C@H]([C@]2([C@@]1([C@H](C(═O)[C@H]2 [C@H](CC(═O)[C@@H]([C@](C)(C)O)O)C)O)C)C)OC(=O)C)C3 RNat217 CC(═O)O[C@H]1CC[C@]2([C@H]([C@]1(C)C)CC[C@@]1([C@@H]2C(═O) C═C2[C@]1(CC[C@@]1(C2═C[C@@](CC1)(C)C(═O)OC)C)C)C)C RNat218 C[C@]12CC[C@](C═C1C1═CC(═O)[C@@H]3[C@]4(CC[C@@H]([C@@] ([C@@H]4CC[C@]3([C@@]1(CC2)C)C)(C)C)O)C)(C)C(═O)OC RNat219 C[C@]12CC[C@](C═C1C1═CC(═O)[C@@H]3[C@]4(CC[C@@H]([C@@] ([C@@H]4CC[C@]3([C@@]1(CC2)C)C)(C)C)OCO)C)(C)C(═O)[O−] RNat220 [C@]123[C@@]4(C2)[C@H]([C@]2([C@](CC4)([C@H]([C@H](C2)O)[C@@]2(O [C@@H](CC2)[C@@](O)(C)C)C)C)C)C[C@@H]([C@H]1[C@]([C@H](CC3)O [C@H]1[C@@H]([C@H]([C@@H](CO1)O)O)OC(═O)C)(C)C)O[C@H]1 [C@@H]([C@@H]([C@H]([C@@H](O1)C)O)O)OC(=O)C RNat221 [C@@]123[C@]4(C2)[C@H]([C@]([C@H](CC4)O[C@H]2[C@@H]([C@H]([C@ @H](CO2)O)O)OC(═O)CC(═O)O)(C)C)CC═C1[C@]1([C@](CC3)([C@H](C(═O) [C@@H]1O)[C@@H](C[C@H]([C@H]1[C@](O1)(C)C)OC(=O)C)C)C)C RNat222 [C@]123[C@H]4[C@@](O[C@H]2OC)([C@H]([C@@H](O[C@H]4C[C@H]1 [C@H]1[C@H](CC3)[C@@]2(C(═CC1)C[C@H](CC2)O[C@H]1[C@@H]([C@H] ([C@@H]([C@H](O1)CO)O)O)O[C@H]1[C@@H]([C@@H]([C@H]([C@@H] (O1)C)OC(═O)c1ccc(cc1)OC)O)O)C)O)/C═C(/C)C)C RNat223 [C@]12(C3═C([C@]4([C@](CC3)([C@H](C[C@H]4O)[C@@H](O)C)C)C)CC [C@H]1[C@]([C@H]([C@@H]([C@H]2O)OC(═O)C[C@@H](C)C)O)(C)C)C RNat224 [C@@]123[C@]([C@@H](C(═C[C@](C1═O)([C@H]1[C@@H](C[C@H]2C)[C@] 1(C)C)C)COC(═O)c1c(NC(═O)c2c(NC(═O)c4c(N(C)C)cccc4)c(ccc2)O)cccc1)O)([C @H](C(═C3)C)O)O RNat225 [C@@]12([C@]([C@@H]([C@@H](O1)[C@@H](C[C@H]([C@H]([C@H]([C@H] (/C═C(/C(═C/C═C/C(═C\C#N)C)C)C)C)O)C)O)OC)O)(C)C)O[C@@H]([C@@H] ([C@H](C2)O)C)C/C═C/c1nc(oc1)[C@@H](CCNC(═O)[C@@H]([C@@H]([C@H] (N(C)C)COC)O)O)C RNat228 C12═CC(═O)[C@@H]3[C@]([C@@]1(CC[C@@]1([C@H]2C[C@](C(═O)O) ([C@@H](C1)O)C)C)C)(CC[C@@H]1[C@@]3(CC[C@@H]([C@@]1(C)C)O)C)C RNat229 [C@@]12([C@]3([C@@H]([C@@]4([C@@H](CC3)[C@]([C@H](CC4)OC(═O)C) (C)C)C)C(═O)C═C1[C@H]1[C@@](CC2)(CC[C@](C1)(C)C)C)C)C RNat231 C[C@]12CC/C(=N\OCC(═O)NCC[C@]3(CCO[C@](C3)(C)C)c3ccccc3)C═C1CC [C@@H]1[C@@H]2CC[C@]2([C@@H]1CC[C@]2(C#C)O)C RNat232 C[C@]12CC/C(=N/OCC(═O)NCC[C@]3(CCO[C@](C3)(C)C)c3ccccc3)C═C1CC [C@@H]1[C@@H]2CC[C@]2([C@@H]1CC[C@]2(C#C)O)C RNat233 [C@H]1([C@]([C@H](O[C@H]2[C@@H]([C@H]([C@H]([C@H](O2)CO)O)O)OC (═O)C)CC[C@]1(OC(═O)C)C)(C)C)CC/C(═C/C[C@@H](/C═C(/[C@H](C[C@H]1 [C@](C(═O)CC═C1C)(C)C)OC(═O)C)C)OC(═O)C)C RNat234 [C@@H]1([C@@H](O[C@@H]([C@H]([C@@H]1O)O)CO)O[C@H]1[C@] ([C@@H]([C@](OC(═O)C)(CC1)C)CC/C(═C/C[C@@H](/C═C(/[C@H](C[C@H] 1[C@](C(═O)CC═C1C)(C)C)OC(═O)C)C)OC(═O)C)C)(C)C)OC(═O)C RNat235 C12═CC(═O)[C@@H]3[C@]([C@@]1(CC[C@@]1([C@H]2C[C@@](C(═O)O) (CC1)C)CO)C)(CC[C@@H]1[C@@]3(CC[C@@H]([C@@]1(C)C)O)C)C RNat236 C[C@H](C/C═C(/c1ccccc1)c1ccccc1)[C@H]1CC[C@@H]2[C@@]1(CC[C@@H]1 [C@@H]2CC═C2[C@@]1(CC[C@@H](C2)OC(═O)C)C)C RNat237 [C@]1([C@@H](C(═O)NC/C═C/C═C(/[C@@H]([C@@H]([C@@H]([C@H] (/C═C/C═C/C═C/C═C(/C(═O)c2c(═O)n(ccc2O)C)C)O)O)C)OC)C)CC)(O [C@@H]([C@@]([C@@H](C1)O)(C)C)/C═C/C═C\C)OC RNat238 C/C(═C\[C@@H]1[C@H]([C@@]1(C)C)C(═O)NCc1ccccn1)C RNat240 c1ccc(cc1)[C@]1(CCN(CC1)C(═O)COc1ccc2c(c1)oc(═O)c1c2CCCC1)C(═O)[O−] RNat241 [C@]123[c@]4([c@@H][c@@]5([c@@H](CC4)[c@][C@H](CC5)O[C@H]4 [C@@H]([C@H]([C@@H]([C@H](O4)CO)O)O[C@H]4[C@@H]([C@H]([C@@H] ([C@H](O4)CO)O)O)O)O)(C)C)C)CC[C@H]1[C@H]1[C@@](C2)(OC3)OC [C@H]([C@@]1(O)C)/C═C(\C)C)C RNat242 CN1CCc2cc3c(c(c2[C@H]1C#CCOc1ccc2c(c1)c1ccccc1o2)OC)OCO3 RNat243 c1cc(cc(c1)[C@@](F)(F)F)c1ccc2n(c1═O)C[C@H]1C[C@@H]2CN(C1)C(═O) Nc1cccc(c1)F RNat244 CC(═O)O[C@H]1CC[C@]2([C@@H]([C@]1(C)C)CC[C@@]1([C@@H]2C(═O) C═C2[C@]1(CC[C@@]1([C@@H]2C[C@@](CC1)(C)C(═O)OC)C)C)C)C RNat245 CC(═O)O[C@H]1CC[C@]2([C@@H]([C@@]1(C)C)CC[C@@]1([C@H]2C(═O) C═C2[C@]1(CC[C@@]1([C@@H]2C[C@@](CC1)(C)C(═O)OC)C)C)C)C RNat246 C[C@]12CC[C@](C[C@@H]1C1═CC(═O)[C@@H]3[C@]4(CC[C@@H]([C@] ([C@H]4CC[C@]3([C@@]1(CC2)C)C)(C)C)O)C)(C)C(═O)OC RNat247 C[C@]12CC[C@](C[C@@H]1C1═CC(═O)[C@H]3[C@]4(CC[C@@H]([C@] ([C@H]4CC[C@]3([C@@]1(CC2)C)C)(C)C)O)C)(C)C(═O)OC RNat248 C[C@H](C)[C@@H](C(=O)Nc1ccc(cc1)O[C@](F)(F)F)NC(=O)N1C[C@H]2C [C@@H](C1)c1cccc(=O)n1C2 RNat249 CSCC[C@@H](C(=O)Nc1ccc(cc1)O[C@](F)(F)F)NC(=O)N1C[C@H]2C[C@@H] (C1)c1cccc(=O)n1C2 RNat250 COc1ccc(cc1)c1ccc2c(c1)C(═O)N1CC[C@@H]([C@H]1C(═O)N2)NC(═O)c1cccc (c1)F

TABLE C.1 Images of 6 conserved cores of several compounds in Table C

TABLE CII Compound ID SMILES Average Activity RNat355829 C═C/C═C/CC1═C(C)[C@H](OC(═O)[C@@H]2 0.99307826 [C@@H](C═C(C)C)C2(C)C)CC1═O RNat241231 C═C/C═C\CC1═C(C)[C@@H](OC(═O)[C@H]2 0.98198923 [C@@H](/C═C(\C)OC(C)═O)C2(C)C)CC1═O RNat282738 C═C/C═C/CC1═C(C)[C@@H](OC(═O)[C@@H]2 0.976296 [C@@H](/C═C(/C)C(═O)OC)C2(C)C)CC1═O RNat156146 C═C/C═C/CC1═C(C)[C@H](OC(═O)[C@H]2[C@H] 0.98735285 (C═C(C)C)C2(C)C)CC1═O RNat005837 CC1(C)[C@@H](C═C(Cl)Cl)[C@H]1C(═O)O 0.98601598 [C@@H](C#N)c1cccc(Oc2ccccc2)c1 RNat156180 C═C/C═C/CC1═C(C)[C@H](OC(═O)[C@H]2[C@H] 0.96289133 (/C═C(/C)C(═O)OC)C2(C)C)CC1═O RNat305444 C/C═C\CC1═C(C)[C@@H](OC(═O)[C@@H]2 0.92737681 [C@@H](/C═C(/C)C(═O)OC)C2(C)C)CC1═O RNat342851 C═C/C═C\CC1═C(C)[C@@H](OC(═O)[C@H]2C 0.9078102 [C@@H]2C═C(C)C)CC1═O RNat163196 CC1(C)[C@@H]([C@](C#N)(OC═O)c2cccc 0.90075687 (Oc3ccccc3)c2)[C@@H]1/C═C(\Cl)C(F)(F)F RNat051960 CCOc1ccc(Oc2c(C)oc3cc(OCc4cccc(Oc5ccccc5)c4) 0.87853138 ccc3c2═O)cc1 RNat346954 C/C═C/CC1═C(C)[C@@H](OC(=O)[C@@H]2 0.84369715 [C@@H](/C═C(\C)OC(C)═O)C2(C)C)CC1═O RNat160096 C/C═C/CC1═C(C)[C@@H](OC(=O)[C@@H]2 0.82286606 [C@@H](/C═C(\C)C(═O)OC)C2(C)C)CC1═O RNat001465 C[C@@H](C(═O)[O−])c1cccc(Oc2ccccc2)c1 0.82214451 RNat303890 C/C═C\CC1═C(C)[C@@H](OC(═O)[C@H]2 0.81808064 [C@@H](C═C(C)C)C2(C)C)CC1═O RNat001067 CCOC(═O)[C@@H]1[C@H](C═C(C)C)C1(C)C 0.79385727 RNat001066 CCOC(═O)[C@H]1[C@H](C═C(C)C)C1(C)C 0.78535436 RNat001064 CCOC(═O)[C@H]1[C@@H](C═C(C)C)C1(C)C 0.78502421 RNat001065 CCOC(═O)[C@@H]1[C@@H](C═C(C)C)C1(C)C 0.78011319 RNat220576 CCOC(═O)C1C(C═C(C)C)C1(C)C 0.77235109 RNat383508 CC(═O)OC(═O)[C@H]1[C@@H](C═C(C)C)C1(C)C 0.72573267 RNat277046 COC(═O)/C(C)═C/[C@H]1[C@H](C(═O)OC)C1(C)C 0.69778205 RNat255691 COC(═O)[C@@H]1[C@@H](C═C(C)C)C1(C)C 0.60695771 RNat044479 [NH3+][C@@H](CC(═O)[O−])c1cccc(Oc2ccccc2)c1 0.57584071 RNat044478 [NH3+][C@H](CC(═O)[O−])c1cccc(Oc2ccccc2)c1 0.57288486 RNat393014 C═C/C═C\CC1═C(C)[C@@H](OC(═O)[C@H]2C 0.55949569 [C@@H]2/C═C(\C)C(═O)OC)CC1═O

In some embodiments, the average activity in Table CII is a predicted average activity.

One or more pesticide compounds may be used alone or in combination with other agents. The compounds of the disclosure may be combined with additional active agent, e.g., other known insecticides and the like. Such compositions may comprise various combinations of compounds as well as varying concentrations of the compound depending upon the insect/pest being targeted.

In some embodiments, the compounds in Table C and Table CII may be employed alone or in mixtures with one another and/or with such solid and/or liquid dispersible carrier vehicles, and/or with other known compatible active agents, including, for example, insecticides, acaricides, rodenticides, fungicides, bactericides, nematocides, herbicides, fertilizers, growth-regulating agents. In some variations, the pesticide compositions are formulated as solutions, emulsions, suspensions, powders, pastes, or granules.

EXAMPLES

The following examples are merely illustrative and are not meant to limit any embodiments of the present disclosure in any way.

Example 1 Repellent Effects of DEET on Mosquitoes

This Example demonstrates that Aedes aegypti detect and avoid DEET primarily using Olfaction.

Materials and Methods

Repellency is tested in mated and starved Ae. aegypti females using a hand-in-glove assay. Briefly, a gloved hand with an opening exposing skin odorants protected by 2 layers of netting was presented to mosquitoes for 5 min inside a cage and video taped for landing and avoidance responses. Mosquitoes were unable to bite due to the outer protective layer of netting and the inner layer of netting was treated with either test compound (10%) or solvent, such that mosquitoes were able to respond to volatiles but unable to make physical contact. The number of mosquitoes present for more than 5 seconds, and the numbers departing during the same period were counted from the videos at minutes 2, 3, 4, and 5 mins and repellency percentage and escape index calculated by comparing with similar numbers in solvent treated controls.

Percentage repellency=100×[1−(mean cumulative number of mosquitoes on the window of treatment for 5 seconds at time points 2, 3, 4, 5 min/mean cumulative number of mosquitoes that remained on window of solvent treatment for 5 seconds at time points 2, 3, 4, 5 min)]. Percentage present=average number of mosquitoes on window for 5 seconds at a given timepoint across trials. All values were normalized to percentage of the highest value for the comparison, which was assigned a 100 percent present. Mean Escape Index=(Average Number of mosquitoes in treatment that landed yet left the mesh during a five second window over the following time points: 2 minutes, 3 minutes, 4 minutes, 5 minutes)/(Average Number of mosquitoes that landed yet left the mesh during a five second window over the same time points in (treatment+control)). Each time point has N=5 trials, 40 mosquitoes per trial, Except for EA, where N=4.

Repellency is also tested in Two-choice heat attraction assay was performed by offering mosquitoes a choice between solvent and DEET treated mesh coupled with a heat stimulus. Heat stimuli for the assay was provided by two Hot Hands® Hand Warmers HH2 (Heat Max, Dalton, Ga.). A pair of heat sources, for test and control was prepared in this manner; 4 hand warmers were simultaneously activated by shaking in gloved hands to 37° C. The hand warmers were fitted snugly into a 100×15 mm petri dish (Fisher) base and covered with 15×15 cm polyester netting secured round the petri dish by a pair or 8 inch plastic cable ties (Gardner Bender, Milwaukee, Wis.) coupling to form a heat pad. Excess netting material was trimmed off round the edges of the petri dish but not the two loose ends of the cable ties. The heat pads were each covered with a 150×15 mm petri dish with a 10×7.5 cm window cut out of its base. This opening was now aligned in and secured in position with the heat pad top with the aid of the loose ends of the cable ties. The pair of large petri dish assembly was placed side by side with the window openings aligned to position. Another pair of 150×15 mm petri dish bases was placed next to the assembly to keep the arena in position and to act as base for test cage. Polyester nets (9×8 cm) treated with 500 μl solvent and DEET 3% concentration were suspended in air and solvent allowed evaporate. Each treated piece was placed between two 10×7.5 cm flexible magnets with 7.5×6.2 cm window frame. Three magnetic window frames were added on top. These solvent and odorant (DEET) treatment net-magnets were simultaneously placed over the 10×7.5 cm openings of the larger petri dishes on the heat pads to form a 2-choice arena. At the start of the assay, a test cage was gently set on its side aligned directly over the 2-choice arena. The pair of petri dish bases and the magnets always maintained a gap of ˜6 mm between the lower treated net and the test mosquito cage screen side thus ensuring no contact between mosquitoes and the treatments. Mosquitoes attracted by heat were thus either exposed to DEET and or acetone (solvent) treatment in a non-contact manner. The solvent and DEET positions were alternated between runs. Mosquito landing choices were during the assay and videos analyzed by counting the number of landings in snapshots of 1 minute interval from the second minute for the duration of the 5 minute trial.

Example 2 In-Silico Screening for Repellent Substitutes for DEET

In this Example, safe natural odors as repellents are identified using an in silico screen.

Materials and Methods

Odor compound libraries: A subset of ˜450,000 volatile compounds was assembled from defined origins including plants, humans, insects (El-Sayed, 2009), food flavours and a fragrance collection (Sigma-Aldrich, 2007) including many additional fruit and floral volatiles (Cork and Park, 1996; Curran et al., 2005; Gallagher et al., 2008; Knudsen et al., 2006; Logan et al., 2008; Meijerink et al., 2000; Zeng et al., 1991; Zeng et al., 1996). Chemicals were also selected from the various metabolite databases, such as the HMDB (http://www.hmdb.ca/), KEGG http://www.genome.jp/kegg/), Yeast Metabolome Database http://www.ymdb.ca), Bovine Metabolome Database (http://bmdb.wishartlab.com), and Plant Metabolites.

Chemical Informatics: Using a Sequential Forward Selection (SFS) approach 18 molecular descriptors from the 3,224 available from the Dragon package (Talete) were selected for their ability to increase the correlation between descriptor values and repellency. The Support Vector Machine (SVM) function from the R package was trained with the 18 descriptors for the training compound set using regression and a radial basis function kernel. We trained SVM models to learn physicochemical features of the confirmed ligands for a subset of ORs whose response profiles are currently better characterized (34 total). Different chemical features were encoded as binary fingerprints, Morgan/Circular, Shortest Path, and Hybridization. Chemical fingerprints can encode up to ˜1000 bits and many are possibly uninformative. Kullback-Leibler (KL) divergence was used to select only those bits that maximized the distance between active and inactive compounds in the training data set of known repellents or pyrethroids. Predictions from these models provided probability scores for new chemicals for each of the two categories. This work relied on the chemistry development kit (CDK) (Steinbeck et al., 2003) as well as its R interface (rcdk) (Guha and Rojas-Chertó). The trained SVM then screened the library of natural compounds we assembled (>450,000) to identify additional chemicals that has one of the two activities.

Results

The 18 optimized-descriptors and SVM method were used to screen in-silico a large chemical library consisting of >440,000 chemicals from a database called eMolecules of putative volatiles. Upon inspection, the top 1,000 predicted compounds (0.23% of hits) were found to represent a structurally diverse group of chemicals that retain some structural features of the known repellents (FIGS. 3A and 3B). Log P values of the 1,000 compounds were computed to identify ones that are predicted to be lipophilic (log P>4.5) thus allowing for selection of other compounds that are less likely to pass through the skin barrier in topical applications (Walker et al., 2003) (FIG. 3B). In addition, the predicted vapor pressures of these chemicals were computed since volatility may predict ability of long-term protection vs. increased spatial domain of action (FIG. 3B). Taken together the results of the screen present a very large collection of novel predicted repellents with desirable properties, identified via a computationally guided search of odor space.

Although the in-silico screen bypasses the challenge of not knowing the protein target, the most significant challenge lies in identifying effective repellent substitutes for DEET that are affordable and safe and that can be rapidly approved for human use. In order to identify compounds that fit these criteria, an in-silico screen was applied to an assembled natural odor library consisting of >3,000 chemicals identified as either originating from plants, insects, or vertebrate species or compounds already approved for human use as fragrances, cosmetics or flavors. Using the trained SVM and optimized descriptor set on the natural library, the top 150 ranked predicted repellent compounds were identified. Predicted repellents share similarity in some parts of the structure while providing a diverse set of compounds (FIG. 3C). For example, several anthranilates and pyrazines were identified that represent novel groups of safe and natural compounds, although such compounds were absent from the training set. These 150 compounds were arranged by predicted log P and vapour pressure values to provide a high-priority list of candidates for behavioral testing (FIG. 3C). 

1. A repellent composition, comprising one or more compounds selected from Table A, Table B, or Table CII.
 2. The composition of claim 1, wherein the composition comprises two or more compounds selected from Table A, Table B and Table CII.
 3. The composition of claim 1, wherein the composition comprises at least one compound selected from Table A, and at least one compound from Table B.
 4. The composition of claim 1, wherein the composition comprises at least one compound selected from Table A, Table B and Table CII, and an additional agent.
 5. The composition of claim 4, wherein the additional agent is a known insect repellent or insecticide.
 6. The composition of claim 1, wherein the composition is formulated as a spray, lotion, foam, gel, suspension, emulsion, mat, embedded fabric, powder, or granule.
 7. A repellent apparatus, comprising: an apparatus containing the composition of claim 1, wherein the apparatus is configured to dispense the composition.
 8. The apparatus of claim 7, wherein the apparatus is a spray container, a heated emanator, a fan-based emanator, an aerosol based emanator, or a vaporizer.
 9. The apparatus of claim 7, wherein the apparatus is affixed on a surface of an object.
 10. A method of repelling an arthropod, comprising: dispensing the composition of claim 1 to expose the arthropod to the composition, thereby repelling the arthropod.
 11. A repellent pesticide composition, comprising one or more compounds selected from Table CII.
 12. The composition of claim 11, wherein the composition comprises two or more compounds from Table CII.
 13. The composition of claim 11, wherein the composition is formulated as a spray, lotion, foam, gel, suspension, mat, embedded fabric, embedded paper, powder, granule, or emulsion.
 14. A repellent pesticide apparatus, comprising: an apparatus containing the composition of claim 11, wherein the apparatus is configured to dispense the composition.
 15. The apparatus of claim 14, wherein the apparatus is a spray container, a heated emanator, a fan-based emanator, an aerosol based emanator, or a vaporizer.
 16. The apparatus of claim 14, wherein the apparatus is affixed on a surface of an object (such as clothes, bednets, furnishings, plants, fruits, entryways, and foods).
 17. A method of treating and/or controlling an arthropod, comprising: applying the composition of claim 11, to a surface of an object.
 18. The method of claim 10, wherein the composition is applied by spraying.
 19. The method of claim 10, wherein the composition is applied using a sprayer, a fan dispenser, a vaporizer, an atomizer, a heated emanator, or an aerosol based emanator.
 20. The method of claim 10, wherein the arthropod is a tick, a bedbug, an insect, a dipteran, a fruit fly and/or a mosquito, agricultural pest insect, a hymenopteran, a cockroach, a spider, or a termite. 